Members of the PhD Program
Our faculty members are outstanding scientists and offer PhD projects - ranging from in vitro to in vivo, and to clinical research - in a stimulating research environment with cutting-edge technologies.
Sandro Krieg is a attending neurosurgeon but also group leader the Department of Neurosurgery at the Technische Universität München. He specializes in the diagnosis and treatment of eloquent brain tumors including pre- and intraoperative mapping techniques. After a stay at UCSF San Francisco he further refined his research group which is mainly focussing on the development of new protocols and techniques of pre- and intraoperative mapping of neurological function. This include navigated transcranial magnetic stimulation (nTMS) and direct electrical stimulation of the cortical and subcortical brain and the application of refined imaging techniques such as nTMS-based tractography and connectomic analyses. For his work he received awards of the German Academy of Neurosurgery, the Neurosurgical Research Foundation of the German Neurosurgical Society (DGNC), and the American Association of Neurological Surgeons (AANS). Currently, his group works mainly on projects by grants of the Wilhelm-Sander foundation and the Else-Kröner-Fresenius foundation. Dr. Krieg has extensive neurophysiological experience and is a reviewer of numerous international neurosurgical but also general neuroscientific journals.
Krieg SM, Sollmann N, Tanigawa N, Foerschler A, Meyer B, Ringel F: Cortical distribution of the human language investigated by navigated transcranial magnetic stimulation in 50 healthy subjects. Brain Struct Funct. 2015 Apr 17. IF 4.567.
Sollmann N, Ille S, Hauck T, Maurer S, Negwer C, Zimmer C, Ringel F, Meyer B, Krieg SM: The impact of preoperative language mapping by repetitive navigated transcranial magnetic stimulation on the clinical course of brain tumor patients. BMC Cancer. 2015 Apr 11;15:261. IF 3.32.
Sollmann N, Tanigawa N, Meyer B, Ringel F, Krieg SM: Language and its right-hemispheric distribution in healthy brains - an investigation by repetitive transcranial magnetic stimulation. Neuroimage. 2014 Nov 15;102 Pt 2:776-88. doi: 10.1016/j.neuroimage.2014.09.002. IF 6.252.
Ille S, Sollmann N, Hauck T, Maurer S, Tanigawa N, Obermueller T, Negwer C, Droese D, Zimmer C, Meyer B, Ringel F, Krieg SM: Combined Non-invasive Language Mapping by nTMS and fMRI and Its Comparison with Direct Cortical Stimulation. J Neurosurg. 2015 Jul;123(1):212-25. doi: 10.3171/2014.9.JNS14929. IF 3.148.
Ille S, Sollmann N, Hauck T, Maurer S, Tanigawa N, Obermueller T, Negwer C, Droese D, Boeckh-Behrens T, Meyer B, Ringel F, Krieg SM: Impairment of preoperative language mapping by lesion location - a fMRI, nTMS, and DCS study. J Neurosurg. 2015 Apr 17:1-11. IF 3.148.
Krieg SM & Tarapore PE, Picht T, Tanigawa N, Houde J, Sollmann N, Meyer B, Vajkoczy P, Berger M, Ringel F & Nagarajan S: Optimal Timing of Pulse Onset for Language Mapping with Navigated Repetitive Transcranial Magnetic Stimulation. Neuroimage. 2014 Oct 15;100:219-36. doi: 10.1016/j.neuroimage.2014.06.016. IF 6.252.
Krieg SM, Sabih J, Bulubasova L, Obermueller T, Negwer C, Janssen I, Shiban E, Meyer B, Ringel F: Preoperative motor mapping by navigated transcranial magnetic brain stimulation improves outcome for motor eloquent lesions. Neuro Oncol. 2014 Sep;16(9):1274-82. doi: 10.1093/neuonc/nou007. IF 6.2.
We study how Alzheimer’s disease develops in the brain on the molecular and cellular level and develop new diagnostic, therapeutic and preventive approaches. Additionally, using proteomics we try to predict possible side effects of Alzheimer-targeted drugs, thus making drug development safer. For our interdisciplinary research we use a variety of modern methods from biochemistry, proteomics, molecular, cellular, neurobiology, in vitro and in vivo models of Alzheimer’s disease. The focus of our research is on proteases of the ADAM (alpha-secretase) and BACE (beta-secretase) families as well as on microglia-dependent inflammatory processes, which have a central role in Alzheimer’s pathogenesis.
Selected examples of our recent research:
ADAM10: We identified this metalloprotease as the Alzheimer’s alpha-secretase, which is able to prevent the molecular pathogenesis leading to Alzheimer’s disease. We found that ADAM10 cleaves numerous additional proteins in neurons. An example is the cell adhesion protein NrCAM, for which we established that cleavage is necessary for the correct outgrowth of axons.
BACE1: We discovered that this major Alzheimer’s drug target cleaves numerous proteins in the nervous system, and has a key role in the function of the brain. An example is seizure protein 6 (SEZ6), where the proteolytic cleavage is required for synapse formation/maintenance.
Neuroproteomics: We have two Orbitrap mass spectrometers. One example of our work is the development of the proteomic hiSPECS method for secretome analyses. Another example is the proteomic analysis of cerebrospinal fluid (CSF), which is now possible with only few microliters of CSF from different organisms.
Pigoni, M., et al. (2020). Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3.
EMBO J, in press.
Rudan Njavro, J., et al. (2020). Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1.
FASEB J, in press.
Fecher, C., et al. (2019). Cell-type-specific profiling of brain mitochondria reveals functional and molecular diversity.
Nat Neurosci 22, 1731-1742.
Lichtenthaler, S.F., and Guner, G. (2019). Pathology-linked protease caught in action.
Science 363, 690-691.
Brummer, T., et al. (2019). NrCAM is a marker for substrate-selective activation of ADAM10 in Alzheimer's disease.
EMBO Mol Med 11.
Parhizkar, S., et al. (2019). Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE.
Nat Neurosci 22, 191-204.
Lichtenthaler, S.F., et al. (2018). Proteolytic ectodomain shedding of membrane proteins in mammals - hardware, concepts, and recent developments.
EMBO J 37.
Colombo, A., et al (2018). Non-cell-autonomous function of DR6 in Schwann cell proliferation.
EMBO J 37.
Kuhn, P.H., et al. (2012). Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons.
EMBO J 31, 3157-3168.
The Misgeld lab studies axon changes in the healthy and in the sick nervous system of living animals. Axons are the long neuronal processes that form synapses and thus interconnect different parts of the nervous system. Obviously, to properly establish wiring in the brain, myriads of axons have to find their targets, or otherwise, axons that connect incorrectly need to be removed.
We are interested in the latter process – not only because such axon dismantling contributes fundamentally to brain development and to the adaptation of our neural circuits to the environment, but also because axons are highly susceptible to pathology. Many common neurological diseases are characterized by early loss of axonal connections – including motor neuron disease, spinal cord injury and multiple sclerosis, all of which we study. By better understanding axon dismantling in development and disease we hope to gain insight into what causes axons to disintegrate in disease.
Breckwoldt M.O., et al. & Misgeld T. (2013) Multi-parametric optical analysis of mitochondrial redox signals during neuronal physiology and pathology in vivo. Nature Medicine in press.
Plucińska G., Paquet D., Hruscha A., Godinho L., Haass C., Schmid B. & Misgeld T. (2012) In vivo imaging of disease-related mitochondrial dynamics in a vertebrate model system. J Neurosci 32, p16203-12.
Marinković P., Reuter M.S., Brill M.S., Godinho L., Kerschensteiner M. & Misgeld T. (2012) Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis. PNAS 109, p4296-301.
Bishop D., Nikic I., Brinkoetter M., Knecht S., Potz S., Kerschensteiner M. & Misgeld T. (2011) Near-infrared branding efficiently correlates light and electron microscopy. Nature Methods 8, p568-70.
Brill M.S., Lichtman J.W., Thompson W., Zuo Y. & Misgeld T. (2011) Spatial constraints dictate glial territories at murine neuromuscular junctions. J Cell Biol 195, p293-30.
Nikić I., Merkler D., Sorbara C., Brinkoetter M., Kreutzfeldt M., Bareyre F.M., Brück W., Bishop D., Misgeld T.* & Kerschensteiner M. (2011) A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nature Medicine 17, p495-9. (* equal senior author)
Misgeld T., Kerschensteiner M., Bareyre F., Burgess R.W. & Lichtman J.W. (2007) In vivo imaging axonal transport of mitochondria in mammals. Nature Methods 4(7), p559-561
Misgeld T. & Kerschensteiner M. (2006) In vivo imaging of the diseased nervous system. Nature Reviews Neuroscience 7(6), p449-6
Kerschensteiner M., Schwab M., Lichtman J.W. & Misgeld T. (2005) In vivo imaging of axonal degeneration and regeneration in the injured spinal cord. Nature Medicine 11, p572-577.
By structural magnetic resonance imaging (MRI), we aim to understand Multiple Sclerosis (MS) at the systemic level. We quantify tissue damage to better monitor the heterogeneous course of MS and to relate these measurements to biomarkers with the ultimate goal to bridge the gap between molecular and systemic neuroscience in the field of MS research.
Schmidt, P, Gaser, C, Arsic, M, Buck, D, Förschler, A, Berthele, A, Hoshi, M, Ilg, R, Schmid, VJ, Zimmer, C, Hemmer, B, Mühlau, M (2012). An automated tool for detection of FLAIR-hyperintense white-matter lesions in Multiple Sclerosis. Neuroimage 59: 3774-83.
Hemmer, B, Mühlau, M (2017). Multiple sclerosis in 2016: Immune-directed therapies in MS - efficacy and limitations. Nat Rev Neurol 13: 72-4.
Righart, R, Pongratz nee Biberacher, V, Jonkman, LE, Klaver, R, Schmidt, P, Buck, D, Berthele, A, Kirschke, JS, Zimmer, C, Hemmer, B, Geurts, JJG, Mühlau, M (2017). Cortical pathology in multiple sclerosis detected by the T1/T2-weighted ratio from routine magnetic resonance imaging. Annals of neurology 82: 519-29.
Grahl, S, Bussas, M, Wiestler, B, Eichinger, P, Gaser, C, Kirschke, J, Zimmer, C, Berthele, A, Hemmer, B, Mühlau, M. (2021). Differential Effects of Fingolimod and Natalizumab on Magnetic Resonance Imaging Measures in Relapsing-Remitting Multiple Sclerosis. Neurotherapeutics 18: 2589-2597.
Bussas, M, Grahl, S, Pongratz, V, Berthele, A, Gasperi, C, Andlauer, T, Gaser, C, Kirschke, JS, Wiestler, B, Zimmer, C, Hemmer, B, Mühlau, M (2022). Gray matter atrophy in relapsing-remitting multiple sclerosis is associated with white matter lesions in connecting fibers. Mult Scler, 28: 900-909.
Our research group investigates how the human brain generates pain. Pain is a vital phenomenon which signals threat and protects the body. However, pain is also influenced by many contextual processes. For instance, our previous experiences, our current expectations and our future goals critically influence the pain we feel. How the brain integrates all these processes and translates them into pain remains, to date, enigmatic. We therefore aim to advance the understanding of these brain processes. Understanding these processes provides basic insights into how the brain translates the outer world into an inner experience. Beyond, such insights are crucial for harnessing these processes for the treatment of pain.
However, pain can also occur for months and years without objective threat to the body. In these cases, pain has lost its protective function but represents a disease in its own right which has detrimental effects on quality of life. Recent evidence indicates that the brain figures prominently in the susceptibility, development and maintenance of chronic pain. Insights into the brain mechanisms of (chronic) pain therefore further the understanding of the pathophysiology of chronic pain and may help to develop biomarkers and novel treatment strategies for chronic pain.
To achieve these goals, we use electroencephalography (EEG) in combination with cutting-edge analysis techniques to investigate the role of neuronal oscillations, or brain rhythms, in the cerebral processing of pain. Moreover, we use non-invasive brain stimulation (transcranial alternating current stimulation, tACS) to modulate neuronal oscillations and alleviate pain.
Ta Dinh S, Nickel MM, Tiemann L, May ES, Heitmann H, Hohn VD, Edenharter G, Utpadel-Fischler D, Tölle TR, Sauseng P, Gross J, Ploner M. Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography. Pain 160:2751-2765, 2019.
May ES, Nickel MM, Ta Dinh S, Tiemann L, Heitmann H, Voth I, Tölle TR, Gross J, Ploner M. Prefrontal gamma oscillations reflect ongoing pain intensity in chronic back pain patients. Hum Brain Mapp 40:293-305, 2019.
Tiemann L, Hohn VD, Ta Dinh S, May ES, Nickel MM, Gross J, Ploner M. Distinct patterns of brain activity mediate perceptual and motor and autonomic responses to noxious stimuli. Nat Commun 9: 4487, 2018.
Davis K, Flor H, Greely H, Iannetti GD, Mackey S, Ploner M, Pustilnik A, Tracey I, Treede RD, Wager TD. Brain imaging tests for chronic pain: medical, and legal, and neuroethical considerations and recommendations. Nat Rev Neurol 13:624-638, 2017.
Ploner M, Sorg C, Gross J. Brain Rhythms of Pain. Trends Cogn Sci 21:100-110, 2017.
We seek to understand the genomic architecture of complex inherited diseases and to study the underlying molecular mechanisms that burden patients with an increased susceptibility. Understanding predisposition allows us to model how environmental factors coalesce to amplify disease manifestation. This knowledge helps us to formulate precise treatments for our patients, taking into consideration their genetic makeup as well as “multi-omic” information. Ultimately, we want to combat disease by predicting susceptibility at an early stage and then preventing the onset.
Our approach is to combine clinical insight gleaned from our patients with high-throughput “omics” analysis such as array-based genotyping, next generation sequencing, and analysis of the proteome, transcriptome and other omics layers. We then investigate the functional relevance of identified markers using cellular and animal models.
We partner with specialized outpatient clinics at the Klinikum rechts der Isar of the Technische Universität München and specialized hospitals in order to learn the needs of our patients. Moreover, with respect for patients and their family’s cooperative spirit, we can transfer the knowledge we gain directly back into the clinic for prevention, self-observation and treatment.
Zech M, Boesch S, Maier EM, IBorggraefe I, Vill K, Laccone F, Pilshofer V, Ceballos-Baumann A, Alhaddad B, Berutti R, Poewe W, Haack TB, Haslinger B, Strom TM and Winkelmann J.Haploinsufficiency of KMT2B, Encoding the Lysine-Specific Histone Methyltransferase 2B, Results in Early-Onset Generalized Dystonia. Am J Hum Genet 2016 Dec 1;99(6):1377-1387.
Zech M, Lam DD, Francescatto L, Schormair B, Salminen AV, Jochim A, Wieland T, Lichtner P, Peters A, Gieger C, Lochmüller H, Strom TM, Haslinger B, Katsanis N, Winkelmann J. Recessive mutations in the α3 (VI) collagen gene COL6A3 cause early- onset isolated dystonia. Am J Hum Genet 2015 Jun 4;96(6):883-93.
Spieler D, Kaffe M, Knauf F, Bessa J, Tena JJ, Giesert F, Schormair B, Tilch E, Lee H, Horsch M, Czamara D, Karbalai N, von Toerne C, Waldenberger M, Gieger C, Lichtner P, Claussnitzer M, Naumann R, Müller-Myhsok B, Torres M, Garrett L, Rozman J, Klingenspor M, Gailus-Durner V, Fuchs H, Hrabě de Angelis M, Beckers J, Hölter SM, Meitinger T, Hauck SM, Laumen H, Wurst W, Casares F, Gómez-Skarmeta JL, Winkelmann J. Restless legs syndrome-associated intronic common variant in Meis1 alters en hancer function in the developing telencephalon. Genome Research 2014 Apr;24(4):592-603.
Schormair B*, Kemlink D*, Roeske D, Eckstein G, Xiong L, Lichtner P, Trenkwalder C, Zimprich A, Högl, Poewe W, Stiasny-Kolster K, Oertel W, Bachmann CG, Paulus W, Peglau I, Vodicka P, Vávrová J, Sonka K, Montplaisir J, Turecki G, Rouleau G, Gieger C, Thomas Illig, H-Erich Wichmann H-E, Holsboer F, Müller-Myhsok B, Thomas Meitinger T, Winkelmann J. Protein-tyrosine Phosphatase Receptor Type Delta (PTPRD) is Associated with Restless Legs Syndrome. Nature Genetics 2008;40:946-948.
The main topic of our research group is the topology of brain networks at the system level in various psychiatric and neurological disorders. We are particularly interested in linking these changes to both underlying biological characteristics and cognitive-behavioral changes, i.e. we perform a three-level approach on brain disorders, where linking the levels of description is the most challenging part.
To illustrate our approach in Alzheimer’s disease (AD): Using functional MRI, we found reduced synchronized activity in posterior parts of the default mode network (DMN) and the executive attention network (EAN) in individuals at risk for AD. Complementary, the density of white-matter fibres in the posterior brain was reduced in AD mainly between regions overlapping with the DMN and EAN as detected by diffusion tensor imaging. Regarding the link between these network changes and cognitive deficits, in early AD patients, the direction and degree of inter-hemispherically dysbalanced metabolism of parietal EAN areas was negatively correlated with the direction and degree of spatial attention bias for visual stimuli. We also found decreases of perfusion and metabolism in the posterior DMN and EAN in AD using arterial-spin-labeling MRI techniques and positron emission tomography.
These studies in AD show how to study brain disorders such as major depression or multiple sclerosis within a three level framework. The overall aim of our research activities is to translate results in advanced imaging diagnostics.
Otti et al: I know the pain you feel-how the human brain’s default mode predicts our resonance to another’s suffering. Neuroscience (in press)
Biswal et al: Toward discovery science of human brain function. Proc Natl Acad Sci U S A. 2010;107(10):4734-9.
Plant et al: Automated detection of brain atrophy patterns based on MRI for the prediction of Alzheimer's disease. Neuroimage. 2010;50(1):162-74
Sorg et al: Impact of Alzheimer's disease on the functional connectivity of spontaneous brain activity. Curr Alzheimer Res. 2009;6(6):541-53
Stroh et al: Impact of magnetic labeling on human and mouse stem cells and their long-term magnetic resonance tracking in a rat model of Parkinson disease. Mol Imaging. 2009;8(3):166-78
Preibisch et al: Neuroanatomical correlates of visual field bias: a sensitive system for detecting potential threats? Brain Res. 2009;31;1263:69-77
Neufang et al: Sex Differences and the Impact of Steroid Hormones on the Developing Human Brain. Cereb Cortex. 2009; 19(2):464-73
Breckwoldt et al: Tracking the inflammatory response in stroke in vivo by sensing the enzyme myeloperoxidase. Proc Natl Acad Sci U.S.A. 2008;105(47):18584-9
Gündel et al: Altered cerebral response to noxious heat stimulation in patients with somatoform pain disorder. Pain. 2008;137(2):413-21
Neufang et al: Developmental changes in neural activation and psychophysiological interaction patterns of brain regions associated with interference control and time perception. Neuroimage. 2008;43(2):399-409
Sorg et al: Selective changes of resting-state networks in individuals at risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2007;104(47):18760-5
The Portugues lab studies how the brain generates behavior. This requires understanding what features of the environment are behaviorally relevant, how the brain is tuned to respond to them, what mechanisms are in place to select appropriate actions and how learning can lead to improved interactions between the animal and its environment. We mainly use the larval zebrafish, a small vertebrate, as a model organism.
We use a highly multidisciplinary approach that uses behavior, functional calcium imaging (both 2-photon and light-sheet microscopy), optogenetics, electrophysiology, computational and theoretical methods to dissect these questions across scales that range from a single neuron to the 100,000 neurons that comprise the whole brain of zebrafish larvae.
Markov DA, Petrucco L, Kist AM, Portugues, R (2021). “A cerebellar internal model calibrates a feedback controller involved in sensorimotor control.” Nature Communications, in press.
Yildizoglu T, Riegler C, Fitzgerald JE*, Portugues R* (2020). “A Neural Representation of Naturalistic Motion-Guided Behavior in the Zebrafish Brain.” Current Biology 30 (12), 2321-2333.
Dragomir EI, Štih V, Portugues R (2020). “Evidence accumulation during a sensorimotor decision task revealed by whole-brain imaging”. Nature Neuroscience. 2020; (23) 85-93.
Kist AM, Portugues R (2019). “Optomotor swimming in larval zebrafish is sriven by global whole-field visual motion and local light-dark transitions.” Cell Reports, 29 (3), 659-670.
Štih V*, Petrucco L*, Kist AM, Portugues R (2019). “Stytra: An open-source, integrated system for stimulation, tracking and closed-loop behavioral experiments”. PLOS Computational Biology, 15 (4), e1006699.
Knogler LD, Kist AM, Portugues R (2019). "Motor context dominates output from purkinje cell functional regions during reflexive visuomotor behaviours". eLife. 2019: e42138.
Knogler LD, Markov AD, Dragomir EI, Štih V, Portugues R (2017). "Sensorimotor representations in cerebellar granule cells in larval zebrafish are dense, spatially organized, and non-temporally patterned". Current Biology. 2017; 27(9): 1288-1302.
Oteiza P, Odstrcil I, Lauder G, Portugues R, Engert F(2017). "A novel mechanism for mechanosensory-based rheotaxis in larval zebrafish". Nature. 2017: 547(7664): 445-448.
Portugues R, Feierstein CE, Engert F, Orger MB (2014). "Whole-brain activity maps reveal stereotyped, distributed networks for visuomotor behavior". Neuron. 2014; 81(6): 1328-1343.
Severi KE*, Portugues R*#, Marques JC, O'Malley DM, Orger MB, Engert F# (2014). “Neural control and modulation of swimming speed in the larval zebrafish.” Neuron 83 (3), 692-707.
Ahrens MB, Li JM, Orger MB, Robson DN, Schier AF, Engert F, Portugues R (2012). Brain-wide neuronal dynamics during motor adaptation in zebrafish. Nature 485: 471-477.
The brain consumes 20% of the human body’s energy budget. Neuronal communication among highly connected brain regions is the main driver of the brain’s energy demands. While we know much about the macroscopic organization of the human brain in specialized regions and brain networks, the energy budget of human brain function is still unclear. Moreover, brain metabolism is heavily disturbed in several neuropsychiatric disorders but the relationship to brain network communication is also unknown.
In my research group, we measure energy consumption of the human brain and relate these to common measures of brain organization. We simultaneously acquire energy metabolism and brain connectivity measures on an integrated PET/MR (Siemens Biograph mMR) scanner. We measure inhibitory and excitatory neurotransmitter levels using 1H-Magnetic Resonance Spectroscopy (MRS) and modulate brain function using non-invasive, stereotactic transcranial magnetic stimulation (TMS).
Methods: hybrid PET/MRI (Positron Emission Tomography, Magnetic Resonance Imaging), Magnetic Resonance Spectroscopy (MRS), Transcranial Magnetic Stimulation (TMS)
- Develop analytical or graph metrical approaches to integrate brain profiles of energy metabolism and network connectivity.
- Study the energy metabolism of brain networks during cognitive tasks.
- Link brain energetics with nutrition and body metabolism.
- Uncover deficient metabolic brain profiles in patients with neuropsychiatric disorders.
The Schäfer Lab focuses on advancing novel stem cell-based technologies to push the boundaries for personalized research on human-specific brain disorders and to identify strategies for facilitating brain repair.
Studying prenatal human brain development remains a challenge due to limited access to live human brain tissue and ethical constraints on research using human embryos. Recent advances in stem cell biology have revolutionized the field of human developmental biology by allowing us to generate three-dimensional models that recapitulate structural organization of various organs, including the brain.
Personalized Human Disease Models to Study Brain Disorders. While specific phenotypes thought to be associated with neuropsychiatric disorders are currently the subject of active research, the question of whether such disease-associated changes represent the consequences of an ongoing and dynamically aberrant developmental process has received less attention. Our lab focuses on dissecting the cellular and developmental origin of mental disorders by using novel approaches that combine comprehensive clinical assessments with patient-specific biological phenotyping. We are particularly interested to dissect cell type-specific principles that govern the dynamic control of human brain development and at the same time introduce a selective vulnerability for human-specific disorders. Identifying “when” and “where” during development a disease signature first emerges has the potential to facilitate pre-symptomatic or, potentially prenatal, diagnosis and risk assessment. We envision that the novel strategies developed here will lead to advances i n mechanism discovery and diagnosis of mental disorders to ensure an early initiation of personalized treatment programs.
Advanced Neuro-Immune Models for Developing Therapies and Guiding Brain Repair. A specialized population of tissue-resident immune cells known as microglia are thought to play a central role in brain development, homeostasis and tissue repair. Our lab is particularly interested to develop technologies that allow us to study how these tissue-resident immune cells communicate with the human brain. We want to understand the cellular and molecular mechanisms by which microglia orchestrate developmental processes in order to devise targeted strategies for facilitating brain repair.
S.T. Schafer, A.C.M. Paquola, S. Stern, D. Gosselin, M. Ku, M. Pena, T.J.M. Kuret, M. Liyanage, A.A. Mansour, B.N. Jaeger, M.C. Marchetto, C.K. Glass, J. Mertens, F.H. Gage
Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons
Nature Neuroscience 22(2), 243–255 https://10.1038/s41593-018-0295-x
[featured as Editor’s Choice in Science Translational Medicine, recommended by F1000Prime]
A.A. Mansour*., S.T. Schafer* & F.H. Gage
Cellular complexity in brain organoids: Current progress and unsolved issues.
Semin. Cell Dev. Biol. [*equal contribution] https://10.1016/j.semcdb.2020.05.013
A. Nott, I.R. Holtman, N.G. Coufal, J.C.M. Schlachetzki, M. Yu, R. Hu, C.Z. Han, M. Pena, J. Xiao, Y. Wu, Z. Keulen, M.P. Pasillas, C. O’Connor, C.K. Nickl, S.T. Schafer, Z. Shen, R.A. Rissman, J.B. Brewer, D. Gosselin, D.D. Gonda, M.L. Levy, M.G. Rosenfeld, G. McVicker, F.H. Gage, B. Ren, C.K. Glass
Brain cell type–specific enhancer-promoter interactome maps and disease risk association
Science 366, 1134–1139. https://10.1126/science.aay0793
J. Mertens, J.R. Herdy, L. Traxler, S.T. Schafer, J.C.M. Schlachetzki, L. Böhnke, D.A. Reid, H. Lee, D. Zangwill, D.P. Fernandes, R.K. Agarwal, R. Lucciola, L. Zhou-Yang, L. Karbacher, F. Edenhofer, S. Stern, S. Horvath, A.C.M. Paquola, C.K. Glass, S.H. Yuan, M. Ku, A. Szücs, L.S.B. Goldstein, D. Galasko, F.H. Gage
Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients
Cell Stem Cell. 28(9), 1533-1548 https://doi.org/10.1016/j.stem.2021.04.004.
S.T. Schafer & F.H. Gage
The When and Where: Molecular and Cellular Convergence in Autism.
Biological Psychiatry 89 (5), 419-420; https://10.1016/j.biopsych.2020.12.016
J.R. Herdy, S.T. Schafer, Y. Kim, Z Ansari, D. Zangwill, M. Ku, A.C.M. Paquola, H. Lee, J. Mertens, F.H. Gage
Chemical modulation of transcriptionally enriched signaling pathways to optimize conversion of fibroblasts into neurons
eLife 8, e41356; https://10.7554/eLife.41356
J.T. Gonçalves*, S.T. Schafer*, F.H. Gage
Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior
Cell 167, 897-914. [*Co-first authors]; https://10.1016/j.cell.2016.10.021
J. Han, H.J. Kim*, S.T. Schafer*, A. Paquola, G.D. Clemenson, A.R. Pankonin, A.M. Denli,
and F.H. Gage
Functional Implications of miR-19 in the Migration of Newborn Neurons in the Adult Brain
Neuron 91(1):79-89 [*Co-second authors]; https://10.1016/j.neuron.2016.05.034
S.T. Schafer*, J. Han, M. Pena, O. von Bohlen und Halbach, J. Peters & F.H. Gage
The Wnt adaptor protein ATP6AP2 regulates multiple stages of adult hippocampal neurogenesis
J Neuroscience 35(12): 4983-4998 [featured article, *corresponding Author]
J. Mertens, Q. Wang, Y. Kim, D.X. Yu, S. Pham, B. Yang, Q. Wang, Y. Zheng, K.E. Diffenderfer, J. Zhang, S. Soltani, T.J. Eames, S.T. Schafer, L. Boyer, M.C. Marchetto, J.I. Nurnberger, J.R. Calabrese, K.J. Ødegaard, M.J. McCarthy, P.P. Zandi, M. Alba, C.M. Nievergelt, The Pharmacogenomics of Bipolar Disorder Study, S. Mi, K.J. Brennand, J.R. Kelsoe†, F.H. Gage† and J. Yao†
Differential Responses to Lithium in Hyperexcitable Neurons from Bipolar Patients
Nature 527(7576):95-9; https://10.1038/nature15526
URL to my full list of published work: https://www.ncbi.nlm.nih.gov/myncbi/1P_N5wwQ050kI/bibliography/public/
Our group is engaged in studies exploring the influence of inflammatory signaling pathways on the pathogenesis and progression of pancreatic diseases. The current focuses of our interest is centered around the signaling pathways NF-κB/Rel and IL-6/gp130/STAT3, which are analyzed in animal models of acute and chronic pancreatitis as well as pancreatic carcinoma.
The aim of our group is to clarify issues with clinical impact using a basic research approach. Mouse models recapitulating major mechanisms of human pancreatic diseases play an important role in our work. With the aid of the Cre-lox technology we investigate the influence of several endogenous factors in these animal models. This genetic methodology allows analyzing the influence of a certain protein on the pathogenesis of pancreatic diseases by inducing organ specific genetic modifications within the pancreas.
Besides our interest in investigating pathogenetic mechanisms of acute pancreatitis, factors predisposing the course and complications of acute pancreatitis are of special interest in our research work.
Another focus of our group is the role of NF-κB/Rel on the course of chronic pancreatitis and fibrogenesis. Besides that, the influence of chronic inflammation on pancreatic carcinogenesis will be analyzed.
The influence of NF-κB/Rel and the IL-6/gp130/STAT3 pathway on the development of precancerous lesions and carcinomas are being investigated in two well-characterized models of pancreatic carcinoma.
Our group is studying the role of the ubiquitin-proteasome system (UPS) in the regulation of the mammalian cell cycle, DNA damage response, and apoptosis. We are particularly interested in how these mechansisms, when deregulated, contribute to the pathogenesis of hematologic malignancies. Our interdisciplinary approach ranges from biochemistry, proteomics and cell biology to mouse genetics.
Fernández-Sáiz, V, Targosz, B.S, Lemeer, S, Eichner, R, Langer, C, Bullinger, L, Reiter, C, SlottaHuspenina, J, Schroeder, S, Knorn, A.M., Kurutz, J, Peschel, C, Pagano, M, Kuster, B, and Bassermann, F. (2013). SCF-Fbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma. Nature Cell Biol 15, 72-81.
Bassermann, F., Eichner, R., Pagano, M. The ubiquitin proteasome system – Implications for cell cycle control and the targeted treatment of cancer. BBA-Mol Cell Res (2013) In press
Dehan, E., Bassermann, F., Guardavaccaro, D., Vasiliver-Shamis, G., Cohen, M., Lowes, K., Dustin, M., Huang, D., Taunton, J., and Pagano, M. (2009). βTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis. Mol Cell 33, 109-116.
Bassermann, F., Frescas, D., Guardavaccaro, D., Busino, L., Peschiaroli, A., Pagano, M. (2008). The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA damage response checkpoint. Cell 134, 256-267.
Frescas, D., Guardavaccaro, D., Bassermann, F., Koyama-Nasu, R., Pagano, M. (2007). The histone demethylase JHDM1B is a nucleolar protein that represses transcription of ribosomal RNA genes. Nature, 450, 309-313.
Busino, L., Bassermann, F., Maiolica, A., Lee, C., Nolan, P. M., Godinho, S. I., Draetta, G. F., and Pagano, M. (2007). SCF-Fbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science 316, 900-904.
Bassermann, F., von Klitzing, C., Muench, S., Bai, R.Y., Kawaguchi, H., Morris, S.W., Peschel, C., and Duyster, J. (2005). NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry. Cell 122, 45-57.
Our lab studies the mechanisms that regulate immunity in cancer and infectious diseases. We have a special interest in the orchestration of tissue immunity by dendritic cells and how it can be harnessed for therapy.
Previous work has identified how dendritic cells cooperate with natural killer cells and T cells within the tumor microenvironment and uncovered suppressive signaling pathways that regulate their activity, identifying new targets for cancer therapy.
In recent years, we have focused on the interaction of Helicobacter pylori with the immune system, specifically on virulence factors involved in immune-evasion. Based on promising new antigens identified in recent years, we are also working on developing H. pylori vaccines based on a combination of new antigens, adjuvants and formulations. We are further exploing how H. pylori contributes to carcinogenesis in the stomach, which virulence factors are employed, and which host signaling pathways are activated during cancer initiation and progression.
The canonical Wnt signaling pathway is essential in developmental processes and plays a crucial role in the regulation of epithelial stem cell self-renewal. Deregulation of this pathway is associated with carcinogenesis, particularly in the gastrointestinal tract. We identified a target gene of the Wnt signaling pathway, RNF43, which is selectively expressed in intestinal stem cells and is overexpressed in colorectal adenomas and a subset of colorectal cancers. Mutations of RNF43 have been identified in several tumor types, suggesting an important role for RNF43 as a tumor suppressor gene. Indeed, depletion of RNF43 expression in colon and gastric cells increases their tumorigenic potential (Neumeyer et al. Carcinogenesis 2019). To further explore the function of RNF43 we have generated two mouse models expressing mutated Rnf43. Mutations in Rnf43 lead to gastric hyperproliferation, which is exacerbated upon H. pylori infection (Neumeyer et al. Cancers 2019). We are also analyzing the mutation status of RNF43 in human gastroinstestinal tumor samples to determine the role of RNF43 in colon and gastric cancer.
Colorectal tumors are the central focus our research, ranking amongst the most frequent tumors in Europe and North America. The initiation and progression of cancer involves multiple steps of genetic and epigenetic alterations, including the loss of function of tumor suppressor genes, and the activation of oncogenes. Our clinical research group tries to understand how the altered signal transduction cascades, like the WNT- and the Ras/MAPK-pathways, contribute to tumor progression and metastasis formation. In addition to these cell-autonomous changes, we are interested in the interactions of cancer cells with the immune system, which may be beneficial or even detrimental for the patient. Genetically defined mouse models have the potential to recapitulate human cancer development, and they allow to address the fundamental question how different genes and signalling pathways cooperate to achieve the goal of malignant transformation. The generation and screening of the preclinical murine models is completed by the analysis of human patient samples, e.g., in the form of primary tumor cell cultures.
Holtorf A (...) KP Janssen. Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy. OncoImmunology (2018) https://doi.org/10.1080/2162402X.2018.1466770
Lobner EM (...) KP Janssen, D Haller. Aberrant ATF6 expression links TRIF-mediated STAT3 activation to colorectal cancer in the context of microbial dysbiosis. Gastroenterology (2018). pii: S0016-5085(18)34816-9. doi: 10.1053/j.gastro.2018.07.028.
Cremonesi E (...) Janssen KP, Borsig L, Iezzi G. Gut microbiota modulate T cell trafficking into human colorectal cancer. Gut (2018) Feb 6. pii: gutjnl-2016-313498. doi: 10.1136/gutjnl-2016-313498.
Raphael BJ (…) Janssen KP (...) Zenklusen JC. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell 2017;32:185-203 e13.
Kistner L (...) Janssen KP. Interferon-inducible CXC-chemokines are crucial immune modulators and survival predictors in colorectal cancer. Oncotarget 2017;8:89998-90012.
Geyer PE (...) Janssen KP. Gastric Adenocarcinomas Express the Glycosphingolipid Gb3/CD77: Targeting of Gastric Cancer Cells with Shiga Toxin B-Subunit. Mol Cancer Ther 2016;15:1008-17.
Buchert M, Rohde F (...) Janssen KP. A hypermorphic epithelial beta-catenin mutation facilitates intestinal tumorigenesis in mice in response to compounding WNT-pathway mutations. Dis Model Mech 2015;8:1361-73.
Zeestraten EC (...) Janssen KP. Specific activity of cyclin-dependent kinase I is a new potential predictor of tumour recurrence in stage II colon cancer. Br J Cancer 2012;106:133-40.
Nitsche U (...) Janssen KP. Integrative marker analysis allows risk assessment for metastasis in stage II colon cancer. Ann Surg 2012;256:763-71; discussion 771.
Janssen KP (...) Robine S. APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology 2006;131:1096-109.
Proteases and their natural inhibitors control virtually all processes of life by controlling and remodeling the proteins in the microenvironment of any cell, its receptors, as well as growth factors. Imbalance of proteases and protease inhibitors promotes detrimental inflammatory processes during infections, tumor growth, and cancer metastasis.
We study the non-canonical function of Tissue-inhibitors of metalloproteinases (TIMPs), namely their newly-discovered potential to act, unexpectedly, as a cell signaling-inducing cytokine, which triggers pro-inflammatory function in immune cells as well as other organ-resident cells.
We have identified the multi-functionality of TIMP-1 and could thereby explain the paradox that TIMP-1 correlates with bad prognosis of many diseases, although its canonical anti-proteolytic activity had led to the prediction that TIMP-1 should inhibit them.
We employ a wide spectrum of technologies encompassing all aspects of molecular cloning/genetic engineering, expression-vector design, biochemistry, cell culture including functional cell-assays, metabolic assays, protein-design and purification, flow-cytometry, histology, in silico-modeling, statistical analyses etc. in order to explore new structure-function relationships between TIMPs and their receptors, which we also identify in the process.
Through cooperation with colleagues in the clinic we constantly validate our data with material from the clinic towards a transfer of new knowledge from bench to the bedside.
Examples of publications from our group (PhD students in bold):
- Hermann, C.D., B. Schoeps, C. Eckfeld, E. Munkhbaatar, L. Kniep, O. Prokopchuk, N. Wirges, K. Steiger, D. Häußler, P. Knolle, E. Poulton, R. Khokha, B.T. Grünwald, I.E. Demir, A. Krüger. TIMP1 expression underlies sex-disparity in liver metastasis and survival in pancreatic cancer. J Exp Med 218 : e20210911, 2021.
- Schoeps, B., C. Eckfeld, L. Flüter, S. Keppler, R. Mishra, P. Knolle, F. Bayerl, J. Böttcher, C.D. Hermann, D. Häußler, A. Krüger. Identification of invariant chain CD74 as a functional receptor of tissue inhibitor of metalloproteinases-1 (TIMP-1). J Biol Chem 297 : 101072, 2021.
- Schoeps, B., C. Eckfeld, O. Prokopchuk, J.P. Böttcher, D. Häußler, K. Steiger, I.E. Demir, P. Knolle, O. Soehnlein, D.E. Jenne, C.D. Hermann, A. Krüger. TIMP1 triggers neutrophil extracellular trap formation in pancreatic cancer. Cancer Res 81 : 3568-3579, 2021.
- Eckfeld, C., D. Häußler, B. Schoeps, C.D. Hermann, A. Krüger. Functional disparities within the TIMP family in cancer: hints from molecular divergence. Cancer Metastasis Rev 38 : 469-481, 2019.
- Grünwald, B., B. Schoeps, A. Krüger. Recognizing the molecular multifunctionality and interactome of TIMP-1. Trends Cell Biol 29 : 6-19, 2019.
- Grünwald, B., V. Harant, S. Schaten, M. Frühschütz, R. Spallek, B. Hoechst, K. Stutzer, S. Berchtold, M. Erkan, O. Prokopchuk, M. Martignoni, I. Esposito, M. Heikenwaelder, A. Gupta, J. Siveke, P. Saftig, P.A. Knolle, D. Wohlleber, A. Krüger, Pancreatic pre-malignant lesions secrete TIMP1, which activates hepatic stellate cells via CD63 signaling to create a pre-metastatic niche in the liver. Gastroenterology 151 : 1011-1024, 2016.
- Seubert, B., B. Grünwald, J. Kobuch, H. Cui, F. Schelter, S. Schaten, J.T. Siveke, N.H. Lim, H. Nagase, N. Simonavicius, M. Heikenwalder, T. Reinheckel, J.P. Sleeman, K.P. Janssen, P. Knolle, A. Krüger. TIMP-1 creates a pre-metastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice. Hepatology 61 : 238-248, 2015.
- Cui, H., B. Seubert, E. Stahl, H. Dietz, U. Reuning, L. Moreno-Leon, M. Ilie, H. Nagase, B. Mari, A. Krüger. Tissue inhibitor of metalloproteinases-1 induces a pro-tumorigenic increase of miR-210 in lung adenocarcinoma cells and their exosomes. Oncogene 34 : 3640-3650, 2015.
Characterization of molecular targets for therapy and identification of molecular determinants for the prediction of therapy response in bladder cancer:
In this project, the group is interested in the evaluation of molecular alterations that allow for stratification of patients in potential responder vs non-responder for specific target therapies in bladder cancer. Methods used are CRISPR-Cas9 gene editing, murine xenograft models, molecular and cell biology assays
Improvement of the replication capacity of oncolotyic adenovirus by identification of combination therapies:
In this project, we identify and characterize target therapies that influence the replicative behaviour of an oncolytic adenovirus
Tong Z, Sathe A, Ebner B, Qi P, Veltkamp C, Gschwend JE, Holm PS, Nawroth R. Functional genomics identifies predictive markers and clinically actionable resistance mechanisms to CDK4/6 inhibition in bladder cancer. J Exp Clin Cancer Res. 2019 Jul 22;38(1):322. doi: 10.1186/s13046-019-1322-9.
Lichtenegger E, Koll F, Haas H, Mantwill K, Janssen KP, Laschinger M, Gschwend J, Steiger K, Black P, Moskalev I, Nawroth R, Holm PS. The oncolytic Adenovirus XVir-N-31 as a novel therapy in muscle-invasive bladder cancer. Hum Gene Ther. 2019 Jan;30(1):44-56. doi:10.1089/hum.2018.026. Epub 2018 Aug 3.
Heck M, Retz M, Bandur M, Souchay M, Vitzthum E, Weirich G, Schuster T, Autenrieth M, Kübler H, Maurer T, Thalgott M, Herkommer K, Gschwend JE and Nawroth R. Molecular lymph node status for prognostic stratification of prostate cancer patients undergoing radical prostatectomy with extended pelvic lymph node dissection. Clin Cancer Res. 2018 Feb 20. pii: clincanres.3771.2017. doi: 10.1158/1078-0432.CCR-17-3771. [Epub ahead of print]
Hedegaard J, et al., Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma. Cancer Cell. 2016 Jun 16. pii: S1535-6108(16)30209-4. doi: 10.1016/j.ccell.2016.05.004.
Heck MM, Thalgott M, Schmid SC, Oh WK, Gong Y, Wang L, Zhu J, Seitz AK, Porst D, Höppner M, Retz M, Gschwend JE, Nawroth R. A 2-gene panel derived from prostate cancer-enhanced transcripts in whole blood is prognostic for survival and predicts treatment benefit in metastatic castration-resistant prostate cancer. Prostate. 2016 May 16. doi: 10.1002/pros.23202.
Sathe A, Koshy N, Schmid SC, Thalgott M, Schwarzenböck SM, Krause BJ, Holm PS, Gschwend JE, Retz M, Nawroth R, CDK4/6-inhibition controls proliferation of bladder cancer and transcription of RB1, The Journal of Urology (2015), doi: 10.1016/j.juro.2015.08.082.
Dr. Reichert’s group focuses on pancreatic development and disease with a strong interest in the molecular underpinnings of cellular plasticity in organogenesis, regeneration, and cancer initiation and dissemination. Using system biology approaches as well as complementary in vitro and in vivo assays, the laboratory addresses questions related to both basic as well as translational biology. Expertise in development of genetic mouse models allows targeted manipulation of candidate genes and their subsequent molecular and phenotypic characterization. Using a combination of high-throughput transcriptional profiling as well as genetic lineage labeling, the laboratory can interrogate both the biochemical and cellular effects of the introduced genetic manipulation.
In particular, the generation of primary pancreatic cells lines from genetically-engineered mouse models and their analysis in three-dimensional culture systems as well as their orthotopic and intravascular re-introduction into mice allows the laboratory to address specific steps in cancer formation and the metastatic cascade.
Reichert M, Takano S, Heeg S, Bakir B, Botta GP, Rustgi AK Gregory P. Botta, Anil K. Rustgi. Isolating Murine Pancreatic Ductal Cells using Magnetic Beads in Development, Regeneration and Cancer, Nature Protocols, 2013 Jun 20;8(7):1354-65. doi: 10.1038/nprot.2013.079.
Reichert M, Takano S, von Burstin J, Kim SB, Lee JS, Ihida-Stansbury K, Hahn C, Heeg S, Schneider G, Rhim AD, Stanger BZ, Rustgi AK. The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis. Genes Dev. 2013 Feb 1;27(3):288-300. doi: 10.1101/gad.204453.112. Epub 2013 Jan 25.
Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, Leach SD, Stanger BZ. EMT and dissemination precede pancreatic tumor formation. Cell. 2012 Jan 20;148(1-2):349-61. doi: 10.1016/j.cell.2011.11.025.
Reichert M, Rustgi AK. Pancreatic ductal cells in development, regeneration, and neoplasia. J Clin Invest. 2011 Dec;121(12):4572-8. doi: 10.1172/JCI57131. Epub 2011 Dec 1. Review.
Reichert M, Saur D, Hamacher R, Schmid RM, Schneider G. Phosphoinositide-3-kinase signaling controls S-phase kinase-associated protein 2 transcription via E2F1 in pancreatic ductal adenocarcinoma cells. Cancer Res. 2007 May 1;67(9):4149-56.
Our group is interested in elucidating the molecular regulation of immune cell development and function through genetic loss and gain of function approaches in the mouse. We investigate B and T lymphocytes and mast cells. Our particular interest is on proteins whose exaggerated functions or malfunctions directly contribute to immunpathologies, such as lymphomas/leukemais, autoimmunity and allergies.
In the context of NF-kB signal transduction we currently focus on the ubiquitin editing enzyme A20/TNFAIP3 and the transcription factor c-Rel. Another central topic is the regulation of mRNA stability by the RING finger proteins Roquin1/2. In addition, we are investigating the role of T cell receptor-expression and signaling on immune-modulating regulatory T (TR) cells and lipid-recognizing NK-like T (NKT) cells.
Heger K, Kober M, Rieß D, Drees C, de Vries I, Bertossi A, Roers A, Sixt M & Schmidt-Supprian M. (2015). A novel Cre recombinase reporter mouse strain facilitates selective and efficient infection of primary immune cells with adenoviral vectors. European Journal of Immunology, 45(6), 1614–1620. doi:10.1002/eji.201545457
Heger K, Fierens K, Vahl JC, Aszodi A, Peschke K, Schenten D, Hammad H, Beyaert R, Saur D, van Loo G, Roers A, Lambrecht BN, Kool M & Schmidt-Supprian M. (2014). A20-deficient mast cells exacerbate inflammatory responses in vivo. PLoS Biology, 12(1), e1001762.
Vahl JC, Drees C, Heger K, Heink S, Fischer JC, Nedjic J, Ohkura N, Morikawa H, Poeck H, Schallenberg S, Rieß D, Hein MY, Buch T, Polic B, Schönle A, Zeiser R, Schmitt-Gräff A, Kretschmer K, Klein L et al. (2014). Continuous T Cell Receptor Signals Maintain a Functional Regulatory T Cell Pool. Immunity, 41(5), 722–736. doi:10.1016/j.immuni.2014.10.012
Vahl JC, Heger K, Knies N, Hein MY, Boon L, Yagita H, Polic B & Schmidt-Supprian M. (2013). NKT cell-TCR expression activates conventional T cells in vivo, but is largely dispensable for mature NKT cell biology. PLoS Biology, 11(6), e1001589. doi:10.1371/journal.pbio.1001589
Chu Y, Vahl JC, Kumar D, Heger K, Bertossi A, Wójtowicz E, Soberon V, Schenten D, Mack B, Reutelshöfer M, Beyaert R, Amann K, van Loo G & Schmidt-Supprian M. (2011). B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood, 117(7), 2227–2236. doi:10.1182/blood-2010-09-306019
Bertossi A, Aichinger M, Sansonetti P, Lech M, Neff F, Pal M, Wunderlich FT, Anders H-J, Klein L & Schmidt-Supprian M. (2011). Loss of Roquin induces early death and immune deregulation but not autoimmunity. The Journal of Experimental Medicine, 208(9), 1749–1756. doi:10.1084/jem.20110578
The pediatric oncology research group focuses on the following two topics of (1) genetic predisposition in childhood cancer and prevention of acute leukemias and (2) translational cellular immunotherapy and oncolytic virotherapy against pediatric sarcoma.
(1) Acute leukemias: Not long ago, genetic predisposition to childhood cancer was purely believed to be attributed to “chance” or “bad-luck”. Now it has been proven that de-novo or inherited cancer predispositions can cause up to 15% of all pediatric tumors. Nevertheless, the overall impact of genetic predispositions is believed to be much higher, with most yet to be discovered. In this regard, we aim to identify and characterize novel disease-causing germline mutations in children with cancer. We further investigate the interplay of genetic predisposition and environmental challenges, including infection and early immune training, in transgenic murine models. By understanding the underlying genetic basis of cancer in combination with training of the innate and adaptive immune system we subsequently aim for early preventive strategies against childhood leukemia.
(2) Pediatric Sarcoma: Pediatric patients with advanced sarcoma carry a poor prognosis, which is why innovative therapy options for these patients are urgently needed. The success of immunotherapy in the treatment of patients with solid tumours is predominantly restricted to entities showing high numbers of tumour infiltrating T cells e.g. directed against somatic mutation derived neo-antigens such as in malignant melanoma. However, unlike melanoma, pediatric cancers such as Ewing’s sarcoma (EwS) are predominantly less immunogenic, probably due to low somatic mutation rates. As therapeutic options for these patients have reached a plateau, innovative new treatment options are warranted. In this regard, our research goal is the introduction of innovative therapy designs such as T cell based immunotherapeutic approaches to improve survival of children and adolecents with high-risk pediatric sarcoma.
Escudero, A., Takagi, M., Auer, F., Friedrich, U. A., Miyamoto, S., Ogawa, A., Imai, K., Pascual, B., Vela, M., Stepensky, P., Yasin, L., Elitzur, S., Borkhardt, A., Pérez-Martínez, A., & Hauer, J. (2022). Clinical and immunophenotypic characteristics of familial leukemia predisposition caused by PAX5 germline variants. Leukemia, 36(9), 2338–2342.
Schedel A, Friedrich UA, Morcos MNF, et al. Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma. Int J Mol Sci. 2022;23(9):5174.
Hauer J, Fischer U, Borkhardt A. Toward prevention of childhood ALL by early-life immune training. Blood. 2021;138(16):1412-1428.
Bhatia, S., Diedrich, D., Frieg, B., Ahlert, H., Stein, S., Bopp, B., Lang, F., Zang, T., Kröger, T., Ernst, T., Kögler, G., Krieg, A., Lüdeke, S., Kunkel, H., Rodrigues Moita, A. J., Kassack, M. U., Marquardt, V., Opitz, F. V., Oldenburg, M., Remke, M., … Hauer, J. (2018). Targeting HSP90 dimerization via the C terminus is effective in imatinib-resistant CML and lacks the heat shock response. Blood, 132(3), 307–320.
Martín-Lorenzo A, Hauer J, Vicente-Dueñas C, et al. Infection Exposure is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5-Inherited Susceptibility. Cancer Discov. 2015;5(12):1328-1343.
Biele E, Schober SJ, Prexler C, et al. Monocyte Maturation Mediators Upregulate CD83, ICAM-1 and MHC Class 1 Expression on Ewing's Sarcoma, Enhancing T Cell Cytotoxicity. Cells. 2021;10(11):3070.
Thiel U, Schober SJ, Ranft A, et al. No difference in survival after HLA mismatched versus HLA matched allogeneic stem cell transplantation in Ewing sarcoma patients with advanced disease. Bone Marrow Transplant. 2021;56(7):1550-1557.
Schober SJ, Thiede M, Gassmann H, et al. MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo. Cells. 2020;9(7):1581.
Thiel U, Schober SJ, Einspieler I, et al. Ewing sarcoma partial regression without GvHD by chondromodulin-I/HLA-A*02:01-specific allorestricted T cell receptor transgenic T cells. Oncoimmunology. 2017;6(5):e1312239.
Kirschner A, Thiede M, Grünewald TG, et al. Pappalysin-1 T cell receptor transgenic allo-restricted T cells kill Ewing sarcoma in vitro and in vivo. Oncoimmunology. 2017;6(2):e1273301.
The focus of my Emmy Noether group is to understand and combat cancer cell resistance to CAR-T cell therapy. We aim to improve this innovative therapeutic approach and extend it to a broader patient population in clinical practice.
Larson, R.C., Kann, M.C., Bailey, S.R., Haradhvala, N.J., Llopis, P.M., Bouffard, A.A., Scarfó, I., Leick, M.B., Grauwet, K., Berger, T.R., Stewart, K., Anekal, P.V., Jan, M., Joung, J., Schmidts, A., Ouspenskaia, T., Law, T., Regev, A., Getz, G., Maus, M.V. (2022). CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours. Nature 604(7906):563-570.
Petri, K.*, Zhang, W.*, Ma, J.*, Schmidts, A.*, Lee, H., Horng, Y.E., Kim, D.Y., Kurt, I.C., Clement, K., Hsu, J.Y., Pinello, L., Maus, M.V., Joung, J.K., Yeh, J.R. (2022). CRISPR prime editing with ribonucleoprotein complexes in zebrafish and primary human cells. Nature Biotechnol. 40(2):189-193. *co-first author
Schmidts, A., Marsh, L.C., Srivastava, A.A., Bouffard, A.A., Boroughs, A.C., Scarfò, I., Larson, R.C., Bedoya, F., Choi, B.D., Frigault, M.J., Bailey, S.R., Leick, M.B., Vatsa, S., Kann, M.C., Prew, M.S., Kleinstiver, B.P., Joung, J.K., Maus, M.V. (2020). Cell-based artificial APC resistant to lentiviral transduction for efficient generation of CAR-T cells from various cell sources. J Immunother Cancer. 8(2):e000990.
Schmidts, A., Wehrli, M., Maus, M.V. (2020). Toward Better Understanding and Management of CAR-T Cell-Associated Toxicity. Annu Rev Med 72:365-382.
Schmidts, A., Ormhoj, M., Choi, B.D., Taylor, A.O., Bouffard, A.A., Scarfo, I., Larson, R.C., Frigault, M.J., Gallagher, K., Castano, A.P., Riley, L.S., Cabral, M.L., Boroughs, A.C., Velasco Cardenas, R.M., Schamel, W., Zhou, J., Mackay, S., Tai, Y.T., Anderson, K.C., Maus, M.V. (2019). Rational design of a trimeric APRIL-based CAR-binding domain enables efficient targeting of multiple myeloma. Blood Adv. 3(21):3248-3260.
Choi, B.D., Yu, X., Castano, A.P., Bouffard, A.A., Schmidts, A., Larson, R.C., Bailey, S.R., Boroughs, A.C., Frigault, M.J., Leick, M.B., Scarfò, I., Cetrulo, C.L., Demehri, S., Nahed, B.V., Cahill, D.P., Wakimoto, H., Curry, W.T., Carter, B.S., Maus, M.V. (2019). CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nature Biotechnol. 37(9):1049-1058.
Schmidts, A., Maus, M.V. (2018) Making CAR T Cells a Solid Option for Solid Tumors. Front Immunol. 9:2593.
The main focus of our research group centers on the engineering and use of novel recombinant, replication-competent oncolytic viral vectors, including vesicular stomatitis virus (VSV) and Newcastle disease virus (NDV), as an immuno-therapeutic platform for cancer therapy. Our research strategies include viral engineering to enhance the tumor specificity and the immune-stimulatory potential of our therapeutic platform, as well as the development of combinatorial approaches with other immunotherapeutics, such as adoptive cell transfer and immune checkpoint blockade. The laboratory aims, not only to develop safe viral vectors that directly kill tumor cells via virus replication, but also to engineer vectors to deliver genes that may further enhance cancer killing though modulation of the tumor microenvironment and stimulation of immune responses against tumor metastases. The molecular basis for mechanisms of potential resistance to viral therapy, as well as the identification of biomarkers to predict the susceptibility of a tumor to onocolytic virus therapy, is also under investigation. We further aim to establish novel imaging modalities for noninvasively tracking viral biodistribution and replication, as well as monitoring tumor responses to viral therapy. We are a translational research lab with a strong focus on clinical development of viral therapies for tumors that are resistant to currently available therapeutics, with an emphasis on gastrointestinal tumors,such as heptocellular carcinoma and pancreatic cancer.
Abdullahi S, Jäkel M, Behrend SJ, Steiger K, Topping G, Krabbe T, Colombo A, Sandig V, Schiergens TS, Thasler WE, Werner J, Lichtenthaler SF, Schmid RM, Ebert O, and Altomonte J. (2018) A novel chimeric oncolytic virus vector for improved safety and efficacy in hepatocellular carcinoma. Journal of Virology (Epub ahead of print).
Krabbe T and Altomonte J. (2018) Fusogenic viruses in oncolytic immunotherapy. Cancers, 10(7).
Altomonte J, Muñoz-Alvarez K, Shinozaki K, Baumgartner C, Kaissis G, Braren R, and Ebert O. (2016) Transarterial administration of oncolytic viruses for locoregional therapy of orthotopic HCC in rats. JoVE (110).
Marozin S, Altomonte J, Muñoz-Álvarez KA, De Toni EN, Thasler WE, Schmid RM, Ebert O. (2015) STAT3 inhibition reduces toxicity of oncolytic VSV and provides a potentially synergistic combination therapy for hepatocellular carcinoma. Cancer Gene Ther, 22(6):317-25.
Muñoz-Álvarez KA, Altomonte J, Laitinen I, Ziegler S, Steiger K, Esposito I, Schmid RM, Ebert O. (2015) PET imgaging of oncolytic VSV expressing the mutant HSV-1 thymidine kinase transgene in a preclinical HCC rat model. Mol Ther, 23(4):728-36.
Altomonte J and Ebert O. (2014) Sorting out Pandora’s box: discerning the dynamic roles of liver microenvironment in oncolytic virus therapy for hepatocellular carcinoma. Frontiers in Immunol, 4:85.
Altomonte J, Marozin S, DeToni EN, Rizzani A, Esposito I, Steiger K, Feuchtinger A, Hellerbrand C, Schmid RM, Ebert O. (2013) Antifibrotic properties of transarterial oncolytic VSV therapy for hepatocellular carcinoma in rats with thioacetamide-induced liver fibrosis. Mol Ther, 21(11):2032-42.
Marozin, S., Altomonte, J., Apfel, S., Dinh, PX., De Toni, EN., Rizzani, A., Nüssler, A., Kato, N., Schmid, RM., Pattnaik, AK., Ebert, O. (2012) Posttranslational modification of vesicular stomatitis virus glycoprotein, but not JNK inhibition, is the antiviral mechanism of SP600125. J Virol, 86(9):4844-55.
We investigate the signaling pathways associated with cellular aging.
Our research centers around cellular aging in normal and disease states, with a particular focus on the molecular and cellular pathogenesis of premature aging diseases such as Hutchinson-Gilford progeria syndrome (HGPS). As means, we combine molecular, cellular biology, genetics, and proteomics to identify signaling pathways associated to cellular aging to develop preventive strategies to delay and/or correct aging processes.
Paradisi M, McClintock D, Boguslavsky RL, Pedicelli C, Worman HJ, Djabali K. (2005) Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stres. BioMed Central Cell Biology 6: 27.
McClintock D, Gordon LD, Djabali K (2006) Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-Lamin A G608G antibody. Proceedings of the National Academy of Sciences 103: 2154-2159.
Cao K, Capell B, Erdos MR, Djabali K, Collins FS (2007) A Lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells. Proceedings of the National Academy of Sciences 104: 4949-4954.
McClintock D, Ratner D, Lokuge M, Owens DM, Gordon LB, Collins FS, Djabali K. (2007) The Mutant Form of Lamin A that Causes Hutchinson-Gilford Progeria Is a Biomarker of Cellular Aging in Human Skin. PLoS ONE 2: e1269.
Marji. J., O'Donoghue SI, McClintock D, Satagopam VP, Schneider R, Ratner D, Worman HJ, Gordon LB, Djabali K. (2010) Defective lamin A-Rb signaling in Hutchinson-Gilford Progeria Syndrome and reversal by farnesyltransferase inhibition. PLoS One 5: e11132.
Olive O, Harten I, Mitchell M, Beers J, Djabali K, Cao K, Erdos MR, Blair C, Funke B, Smoot L, Gerhard-Herman M, Machan JT, Kutys R, Virmani R, Collins FS, Wight TN, Nabel EG, Gordon LB. (2010) Cardiovascular Pathology in Hutchinson-Gilford Progeria: Correlation With the Vascular Pathology of Aging. Arteriosclerosis, Thrombosis, and Vascular Biology 30, 2031-2039.
Wenzel, V, Roedl D, Gabriel D, Gordon L.B, Herlyn M, Schneider R, Ring, Djabali K. (2012). Naïve adult stem cells from patients with Hutchinson-Gilford progeria syndrome express low levels of progerin in vivo. Biology Open, 1-11.
The working group "Molecular Intervention" is interested in therapeutic approaches intervening in the molecular signaling of cardiovascular diseases. In doing so, a broad spectrum of cardiological diseases are covered by large animal models, e.g. ischemia/reperfusion, chronic ischemic heart disease, heart hypertrophy and hereditary cardiomyopathy. Besides pharmocological agents, Adeno-associated viruses (AAV)are used as vehicles to intervene in pathological signalling pathways. They are able to transduce efficiently and lastingly the myocardium by low activation of the immune system.
The purification, renewal and differentiation of native cardiac progenitors would form a mechanistic underpinning for unraveling steps for both cardiac lineage formation and regeneration, and their links to forms of congenital and adult cardiac diseases. Further understanding of molecular cascades that are active during cardiac formation are proving useful for the identification and manipulation of embryonic and adult cardiac stem/progenitor cells that offer opportunities for the treatment of adult and congenital heart disease. Lineage tracing studies documented that the LIM-homeodomain transcription factor Islet-1 (Isl1) represents an embryonic marker for a genetically distinct population of undifferentiated master heart progenitors that give rise to all of the major muscle and non-muscle cell lineages of the heart. Utilizing ESCs and iPSCs that harbor knock-ins of reporter genes under the expression control of the genomic isl1 locus allows the isolation of Isl1+ cardiac progenitors from mouse and human pluripotent stem cell systems during in vitro cardiogenesis. These genetic systems should allow the rapid and direct identification of signaling pathways which guide the formation, renewal, and diversification of ISL1+ heart progenitors into distinct heart cell lineages, and forms a biological foundation for tissue engineering of specific heart components.
Our research strategies focus on technologies for improving vascularisation of tissue in vivo and matrices for tissue regeneration (bone, skin, fat, nerves) in vitro. We have developed different approaches including protein-, cell- and biomaterial based technologies in different animal models, especially in rodents. Clinically, we work on GMP-processes to implement our experimental results into clinical practice with protein- and cell-based protocols, including cell-based gene transfer technologies.
Rejuvenation Res. in press: Recombinant human erythropoietin plays a pivotal role as a topical stem cell activator to reverse effects of damage to the skin in aging and trauma. Bader A and Machens HG
Handchir Mikrochir Plast Chir. 2010 Mar 10. [Epub ahead of print]: Calvarial Reconstruction by Customized Bioactive Implant. Probst FA, Hutmacher DW, Müller DF, Machens HG, Schantz JT.
Biomaterials. 2009 Oct;30 (30):5918-26. The use of glandular-derived stem cells to improve vascularization in scaffold-mediated dermal regeneration. Egana JT, Danner S, Kremer M, Rapoport DH, Lohmeyer JA, Dye JF, Hopfner U, Lavandero S, Kruse C, Machens HG.
Biomaterials. 2009 Feb;30 (5):789-96. The influence of pancreas-derived stem cells on scaffold based skin regeneration. Salem H, Ciba P, Rapoport DH, Egana JT, Reithmayer K, Kadry M, Machens HG, Kruse C.
J Cell Mol Med. 2010 Mar;14 (3):587-99. Non-viral VEGF(165) gene therapy--magnetofection of acoustically active magnetic lipospheres (magnetobubbles) increases tissue survival in an oversized skin flap model. Holzbach T, Vlaskou D, Neshkova I, Konerding MA, Wörtler K, Mykhaylyk O, Gänsbacher B, Machens HG, Plank C, Giunta RE.
Tissue Eng Part A. 2009 May;15 (5):1191-200. Use of human mesenchymal cells to improve vascularization in a mouse model for scaffold-based dermal regeneration. Egana JT, Fierro FA, Krüger S, Bornhäuser M, Huss R, Lavandero S, Machens HG.
Our group focuses on a deeper mechanistic understanding of cancer biology using novel cutting edge genetic engineering, targeting and large-scale genome-wide screening technologies. We are studying the following fundamental biologically and clinically relevant aspects of cancer: how it develops, progresses, spreads to distant sites, and why it becomes resistant to anti-cancer therapies. The translation of new biological understanding into clinically useful diagnostic and therapeutic approaches is a key mission of the lab.
Mueller S, Engleitner T, Maresch R, ..., Saur D*, Rad R* (2018). Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature. 554:62-68. *joint senior authors.
Schneider G, Schmidt-Supprian M, Rad R, Saur D (2017). Tissue-specific tumorigenesis – context matters. Nat Rev Cancer. 17:239-253
Maresch R, Mueller S, Veltkamp C, ..., Bradley A, Saur D*, Rad R* (2016). Multiplexed pancreatic genome engineering and cancer in-duction by transfection-based CRISPR/Cas9 delivery in mice. Nat Commun. 7:10770. *joint senior authors.
Rad R, Rad L, Wang W, ..., Liu P, Saur D, Bradley A (2015). A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer. Nat Genet. 47:47-56.
Schönhuber N, Seidler B, Schuck K, ..., Schmid RM, Schneider G, Saur D (2014). A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. Nat Med. 20:1340-7.
Eser S, Reiff N, Messer M, ..., Schmid RM, Schneider G, Saur D (2013). Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell, 23:406-20.
Rad R, Cadiñanos J, ..., Liu P, Saur D*, Bradley A* (2013). A genetic progression model of BrafV600E-induced intestinal tumourigenesis reveals targets for thera-peutic intervention. Cancer Cell. 24:15-29. * equal contribution.
Klein S, Seidler B, Kettenberger A, Sibaev A, Rohn M, Feil R, Allescher HD, Vanderwinden JM, Hofmann F, Schemann M, Rad R, Storr MA, Schmid RM, Schneider G, Saur D. Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity. Nat Commun. 4:1630.
von Werder A, Seidler B, Schmid RM, Schneider G, Saur D (2012). Production of avian retroviruses and tissue-specific somatic retroviral gene transfer in vivo using the RCAS/TVA system. Nat Protoc. 7:1167-83.
The major research objectives of our laboratory are to understand the molecular mechanisms of pancreatic carcinogenesis and tumor maintenance. We use transgenic and knockout approaches to investigate the role of cancer-relevant mutations in mice.
Our group focuses on the role of reactive oxygen species in chronic inflammation and the link between inflammation and tumor development.
Chronic pancreatitis: Patients suffering from chronic pancreatitis are at increased risk of developing pancreatic cancer. We have established genetic models of chronic pancreatitis. These models are used to investigate the role of inflammation in pancreatic tumor development as well as to test preventive and therapeutic approaches.
Tumor maintenance: Tumor viability is maintained by more genetic alterations than have initially led to tumor development. Identifying these changes will help to understand the cooperative effect of multiple oncogenic changes. Approaches include identification of critical cellular components and characterization of their functions using molecular, cellular and genetic methods.
Mazur P, Einwächter H, Lee M, Sipos B, Nakhai H, Rad R, Zimber-Strobl U, Strobl L, Radtke F, Kloeppel G, Schmid RM, Siveke J. Notch2 is required for PanIN progression and development of pancreatic ductal adenocarcinoma. PNAS (in press).2010.
von Burstin J, Eser S, Paul MC, Seidler B, Brandl M, Messer M, von Werder A, Schmidt A, Mages J, Pagel P, Schnieke A, Schmid RM, Schneider G, Saur D. E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. Gastroenterology. 2009 Jul;137(1):361-71
Siveke JT, Lubeseder-Martellato C, Lee M, Mazur PK, Nakhai H, Radtke F, Schmid RM. Notch signaling is required for exo¬crine regeneration after acute pancreatitis. Gastroenterology. 2008 Feb;134(2):544-55.
Siveke JT, Einwächter H, Sipos B, Lubeseder-Martellato C, Klöppel G, Schmid RM. Concomitant pancreatic activation of Kras(G12D) and Tgfa results in cystic papillary neoplasms reminiscent of human IPMN. Cancer Cell. 2007 Sep;12(3):266-79.
Algül H, Treiber M, Lesina M, Nakhai H, Saur D, Geisler F, Pfeifer A, Paxian S, Schmid RM. Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis. J Clin Invest. 2007 Jun;117(6):1490-501.
Our group is exploring how different immune cell signals contribute to the development of different B cell malignancies and how metabolic cues support the escape of B cell intrinsic checkpoint that usually prevent transformation. The current focuses of our laboratory are on the transformation of chronic lymphocytic leukemia to an aggressive lymphoma as well as the plasma cell disorder multiple myeloma. Mouse models recapitulating major mechanisms of the human diseases play an important role in our work. Using transgenic mouse lines with the Cre-loxP technology, we investigate the influence of several (signalling) factors on the development and the progression of diseases in these animal models.
CLL and Richter’s Transformation:
We have established a model to mimic the transformation of CLL to an aggressive lymphoma by additional oncogene activation. We have observed that acute oncogene activation in CLL cells induces cell death in the vast majority of CLL cells (Ecker et al, Nat. Comm. 2021). However, some cells survive and then outgrow the initial tumor and show several features of Richter cells. We now aim to use this model to understand which mechanism support the survival of the cells giving rise to the aggressive lymphoma and verify these in human samples. Understanding those mechanisms may help to prevent or treat the aggressive Richter lymphoma, which has a very poor clinical outcome.
CLL and drug resistance:
Another focus of our group is to understand how different signals from the microenvironment support the expansion of CLL cells despite the highly effective treatment with the BTK inhibitor ibrutinib or the BCL2 inhibitor venetoclax. We investigate strategies to prevent these interactions and to breach the strong immunosuppressive character of CLL cells, which then are tested in combination with immunotherapy (CAR T cells and checkpoint inhibition) in CLL.
We have generated a novel mouse model that reflects the human plasma cell disorder multiple myeloma in several ways. To gain insight into the pathogenesis of this deadly disease, we aim to analyse which factors contribute to the disease evolution in our model and compare it with data of human myeloma samples.
Our Emmy Noether group is focused on engineering CRISPR technologies for research and therapeutic applications in cardiovascular medicine. We also aim to apply the newest gene editing tools in stem cells, ex vivo tissues, and organoids. The lab is located at the TranslaTUM Organoid Hub of the Center for Organoid Systems (COS). Please reach out to Julian, if you’re interested in learning more!
Lab website: http://grunewaldlab.org
Hsu, J.Y., Grünewald, J., Szalay, R., Shih, J., Anzalone, A.V., Lam, K.C., Shen, M.W., Petri, K., Liu, D.R., Joung, J.K., Pinello L. - PrimeDesign software for rapid and simplified design of prime editing guide RNAs. Nature Communications 12, 1034 (2021)
Kurt, I. C., Zhou, R., Iyer, S., Garcia, S. P., Miller, B. R., Langner, L. M., Grünewald, J.,* & Joung, J. K.* - CRISPR C-to-G base editors for inducing targeted DNA transversions in human cells. Nature Biotechnology 39(1), 41-46 (2021) *co-corresponding author
Grünewald, J.*, Zhou, R.*, Lareau, C. A., Garcia, S. P., Iyer, S., Aryee, M. J., & Joung, J. K. - A Dual-Deaminase CRISPR Base Editor Enables Concurrent Adenine and Cytosine Editing. Nature Biotechnology. 38(7), 861-864 (2020) *co-first author
Grünewald, J., Zhou, R., Iyer, S., Lareau, C. A., Garcia, S. P., Aryee, M. J., & Joung, J. K. - CRISPR DNA base editors with reduced RNA off-target and self-editing activities. Nature Biotechnology, 37(9), 1041–1048 (2019)
Grünewald, J., Zhou, R., Garcia, S. P., Iyer, S., Lareau, C. A., Aryee, M. J., & Joung, J. K. Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors. Nature, 569(7756), 433–437 (2019)
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The endosomal system plays an essential role in maintaining cell homeostasis by controlling cellular signaling, nutrient sensing, cell polarity and cell migration. However, its place in the regulation of tissue, organ and whole body physiology and metabolism is less well understood. Therefore, the Zeigerer group investigates the novel link between endocytosis and metabolism with impact on metabolic disease such as type-2 diabetes and fatty liver disease. In particular, we are interested in how components of the endo-lysosomal system influence glucose and lipid metabolism in the liver. On the other hand, we investigate how metabolic cues, such as the fasting/feeding transition and metabolic abnormalities alter endo-lysosomal function. To address these research areas, the lab uses primary mouse and human hepatocyte 3D cultures, where hepatocytes regain cell polarity and liver-specific metabolic functions, as well as in vivo liver specific nanoparticle mediated knockdown technology, coupled with biochemistry, cellular metabolic assays, high-resolution confocal microscopy and quantitative imaging. This approach enables to bridge two so far unconnected research areas, intracellular trafficking and metabolism, leading to the establishment of a new research direction and a simultaneous development of a new class of therapeutic target structures for metabolic diseases.
Our research at the Chair of Translational Genomics leverages big data in genetics and genomics for medically important human traits. We aim to translate insights from genomics into mechanisms of disease development and progression, shortening the path to translation and empowering precision medicine. We integrate information gleaned from deep molecular, genomics and epidemiological approaches to address important biomedical research challenges. Our work is underpinned by data generation at scale and by the development of computational genomics toolkits to analyse the wealth of information.
The goal of our research is to improve individual patient diagnostics and therapy response monitoring in oncology. We employ laboratory model systems and advanced computational methods to develop and validate imaging-derived biomarkers.
Our preclinical work comprises the characterization of advanced tumor models including genetically engineered mouse models and PDX, the development of novel multi-modal imaging techniques (e.g. Magnetic Resonance Spectroscopic Imaging, Phase Contrast Computed Tomography) and the integrated anaylsis of imaging and morphomolecular data.
Our clinical work includes the curation of large, multi-institutional image and clinical data repositiores, the integrated modelling of image data and metadata for the improved non-invasive characterization of tumor heterogeneity and the prediction of individual patient therapy response and survival
Multiparametric Modelling of Survival in Pancreatic Ductal Adenocarcinoma Using Clinical, Histomorphological, Genetic and Image-Derived Parameters.
Kaissis GA, Jungmann F, Ziegelmayer S, Lohöfer FK, Harder FN, Schlitter AM, Muckenhuber A, Steiger K, Schirren R, Friess H, Schmid R, Weichert W, Makowski MR, Braren RF.
J Clin Med. 2020 Apr 25;9(5):1250. doi: 10.3390/jcm9051250.
Combined DCE-MRI- and FDG-PET enable histopathological grading prediction in a rat model of hepatocellular carcinoma.
Kaissis GA, Lohöfer FK, Hörl M, Heid I, Steiger K, Munoz-Alvarez KA, Schwaiger M, Rummeny EJ, Weichert W, Paprottka P, Braren R.
Eur J Radiol. 2020 Mar;124:108848. doi: 10.1016/j.ejrad.2020.108848. Epub 2020 Jan 23. PMID: 32006931
Co-clinical Assessment of Tumor Cellularity in Pancreatic Cancer.
Heid I, Steiger K, Trajkovic-Arsic M, Settles M, Eßwein MR, Erkan M, Kleeff J, Jäger C, Friess H, Haller B, Steingötter A, Schmid RM, Schwaiger M, Rummeny EJ, Esposito I, Siveke JT, Braren RF.
Clin Cancer Res. 2017 Mar 15;23(6):1461-1470. doi: 10.1158/1078-0432.CCR-15-2432. Epub 2016 Sep 23. PMID: 27663591
Our research focuses on the development of novel Magnetic Resonance Imaging (MRI) acquisition and reconstruction methods with an emphasis on the extraction of quantitative imaging biomarkers. The developed methods are being translated into clinical studies for improving the diagnosis, the therapy monitoring, and the understanding of disease pathophysiology in the diseases of the musculoskeletal system (e.g. osteoporosis, neuropathies, neuromuscular diseases), in metabolic dysfunction (e.g. obesity, diabetes, cachexia) and in body oncology.
D. Franz, M. N. Diefenbach, F. Treibel, D. Weidlich, J. Syväri, S. Ruschke, M. Wu, C. Holzapfel, T. Drabsch, T. Baum, H. Eggers, E. J. Rummeny, H. Hauner, D. C. Karampinos, Differentiating supraclavicular from gluteal adipose tissue based on simultaneous PDFF and T2* mapping using a 20-echo gradient-echo acquisition, Journal of Magnetic Resonance Imaging, 50:424, 2019
D. Weidlich, J. Honecker, O. Gmach, M. Wu, R. Burgkart, S. Ruschke, D. Franz, B. H. Menze, T. Skurk, H. Hauner, U. Kulozik, D. C. Karampinos, Measuring large lipid droplet sizes by probing restricted lipid diffusion effects with diffusion-weighted MRS at 3T, Magnetic Resonance in Medicine, 81:3427, 2019
M. N. Diefenbach, J. Meineke, S. Ruschke, T. Baum, A. Gersing, D. C. Karampinos, On the sensitivity of quantitative susceptibility mapping for measuring trabecular bone density, Magnetic Resonance in Medicine, 81:1793, 2019
S. Ruschke, H. Kienberger, T. Baum, H. Kooijman, M. Settles, A. Haase, M. Rychlik, E. J. Rummeny, D. C. Karampinos, Diffusion-weighted STEAM MRS to measure fat unsaturation in regions with low proton-density fat fraction, Magnetic Resonance in Medicine, 75:32-41, 2016
B. Cervantes, J. S. Bauer, F. Zibold, H. Kooijman, M. Settles, A. Haase, E. J. Rummeny, K. Wörtler, D. C. Karampinos, Imaging of the lumbar plexus: Optimized refocusing flip angle train design for 3D TSE, Journal of Magnetic Resonance Imaging, 43:789, 2016
C. Cordes*, M. Dieckmeyer, B. Ott, J. Shen, S. Ruschke, M. Settles, C. Eichhorn, J. S. Bauer, H. Kooijman, E. J. Rummeny, T. Skurk, T. Baum, H. Hauner, D. C. Karampinos, MR-detected changes in liver fat, abdominal fat, and vertebral bone marrow fat after a four-week calorie restriction in obese women, Journal of Magnetic Resonance Imaging, 42:1272-1280, 2015
In multiple sclerosis infiltrating immune cells damage resident cells of the nervous system such as neurons and oligodendrocytes. This structural damage is responsible for the irreversible functional deficits in patients with multiple sclerosis. The aim of our work is to better understand how immune cells cause nervous system damage and use this knowledge to develop novel treatment strategies that limit tissue damage in multiple sclerosis.
We use in vivo imaging techniques in combination with viral and transgenic labelling to follow in real-time the cellular and molecular interactions that underlie tissue damage in animal models of multiple sclerosis. Based on these insights into the in vivo pathogenesis we then use genetic and pharmacological manipulations to design and evaluate new therapeutic strategies that foster tissue protection and repair.
Breckwoldt MO et al. Multi-parametric optical analysis of mitochondrial redox signals during neuronal physiology and pathology in vivo. Nature Medicine in press
Romanelli E et al. Cellular, subcellular and functional in vivo labeling of the spinal cord using vital dyes. Nature Protocols 8: 481-90 (2013)
Marinkovic P et al. Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis. PNAS 109: 4296-301 (2011)
Bishop D et al. NIRB – near infrared branding efficiently correlates light and electron microscopy. Nature Methods 8: 568-70 (2011)
Bareyre FM et al. In vivo imaging reveals a phase-specific role of STAT3 during CNS and PNS axon regeneration. PNAS 108: 6282-7 (2011)
Nikic I et al. A reversible form of axon damage in multiple sclerosis and its animal model. Nature Medicine 17: 495-9 (2011)
Misgeld T et al. Imaging axonal transport of mitochondria in vivo. Nature Methods 4: 559-61
Misgeld T & Kerschensteiner M. In vivo imaging of the diseased nervous system. Nature Reviews Neuroscience 7: 449-463 (2005)
Kerschensteiner M et al. In vivo imaging of axonal degeneration and regeneration in the injured spinal cord. Nature Medicine 11: 572-577 (2005)
Bareyre FM et al. Transgenic tracing of the corticospinal tract: a new tool to study axonal regeneration and remodelling. Nature Medicine 11: 1355-1360 (2005)
Our research investigates alterations in brain structure and function in psychiatric disorders. The focus is on obsessive-compulsive disorder and schizophrenia which are both characterized by structural brain changes and alterations in brain activity and behavior. Patients with schizophrenia suffer from positive symptoms such as hallucinations as well as negative symptoms such as attentional and learning deficits which lead to severe everyday life impairments. Using functional MRI and diffusion tensor imaging (DTI) we try to find out more about the structural and functional correlates of these deficits. We moreover apply multi-modal imaging combining functional MRI, structural MRI and DTI to investigate the association between alterations in white matter structure, gray matter structure as well as functional activation and functional connectivity in patients with obsessive-compulsive disorder. As there is first evidence indicating that the different symptoms or symptom dimensions of the disorder may be mediated by partially distinct neurobiological entities finding out more about symptom-specific functional and structural alterations constitutes another major aim of our research.
One of the focus areas of Prof. Gabriele Multhoff’s research work is the development of innovative cell-, molecule- and antibody-based targeted immunotherapies based on heat shock proteins (SFB824). The aim is to combine these new therapeutic approaches with conventional radiation therapy and chemotherapy. Her current research work has led to a randomized, multicenter clinical phase II study entitled “Targeted NK cell-based adjuvant immunotherapy for the treatment of patients with non-small cell lung carcinoma (NSCLC) after radiochemotherapy” funded by the BMBF. To stratify patients who most likely will benefit from Hsp70-targeting therapies, her group established a novel screening test (lipHsp70 ELISA, patent) to quantify liposomal, tumor-derived Hsp70 and a method to isolate circulating tumor cells (CTCs) after mesenchymal transition in the blood of patients. Liposomal Hsp70 provides a promising biomarker for viable tumor mass in different tumor entities and CTCs in the blood are presently evaluated as valuable tools for prediction of clinical responses and therapy resistance of cancer.
Her research interests also include the application of novel in vivo imaging techniques such as intraoperative, fluorescence molecular tomography (FMT), multispectral optoacoustic tomography (MSOT) and PET/CT in small animals after CT-guided irradiation of tumors using the small animal radiation research platform SARRP (DFG) and the analysis of cellular, molecular biological and immunological mechanisms in tumor and normal cells including primary endothelial cells after exposure to radiation, as well as the development of innovative nanoparticle-based theranostica.
Chalmin, F., Ladoire, S., Mignot, G., Vincent, J., Bruchard, M., Remy-Martin, J. P., Boireau, W., Rouleau, A., Simon, B., Lanneau, D., De, T. A., Multhoff, G., Hamman, A., Martin, F., Chauffert, B., Solary, E., Zitvogel, L., Garrido, C., Ryffel, B., Borg, C., Apetoh, L., Rebe, C., and Ghiringhelli, F. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J. Clin. Invest 120(2): 457-471, 2010.
Stangl S, Varga J, Freysoldt B, Trajkovic-Arsic M, Siveke JT, Greten FR, Ntziachristos V, Multhoff G. Selective in vivo Imaging of syngeneic, spontaneous and xenograft tumors using a novel tumor cell-specific Hsp70 peptide-based probe. Cancer Res 74(23): 6903-6912, 2014.
Stangl S, Tei L, De Rose F, Reder S, Martinelli J, Sievert W, Shevtsov M, Öllinger R, Rad R, Schwaiger M, D`Alessandria C, Multhoff G. Preclinical evaluation of the Hsp70 peptide tracer TPP-PEG24-DFO[89Zr] for tumor-specific PET/CT imaging. Cancer Res 78(21): 6268-628, doi: 10.1158/0008-5472.CAN-18-0707, 2018.
Shevtsov M, Stangl S, Nikolaev B, Yakovleva L, Marchenko Y, Tagaeva R, Sievert W, Pitkin E, Mazur A, Tolstoy P, Galibin O, Ryzhov V, Steiger K, Smirnov O, Khachatryan W, Chester K, Multhoff G. Granzyme B functionalized nanoparticles targeting membrane Hsp70-positive tumors for multimodal cancer theranostics. Small 15(13): e1900205, doi: 10.1002/smll.201900205, 2019.
My laboratory is focused on developing next generation molecular imaging and control technology for neuroscience.
Our goal is to obtain dynamic information on molecular events in neurons to monitor neural activity across entire intact brains and thereby complement optical methods mostly restricted to invasive imaging of small areas of the brain surface.
To this end, we employ bioengineering and genetic techniques, chemistry as well as nanotechnology to generate molecular contrast agents that translate molecular processes of interest into dynamic signals detectable by non-invasive imaging technology such as Magnetic Resonance Imaging (MRI) or Optoacoustics. Complementarily, we work on molecular devices to control cellular processes non-invasively.
We validate this methodology with a variety of biochemical and cell culture methods and apply it to fundamental questions in neuroscience and preclinical models of neuropsychiatric diseases.
Stiel, A. C. et al. High-contrast imaging of reversibly switchable fluorescent proteins via temporally unmixed multispectral optoacoustic tomography. Optics letters 40, 367–370 (2015).
Westmeyer, G. G., Emer, Y., Lintelmann, J. & Jasanoff, A. MRI-Based Detection of Alkaline Phosphatase Gene Reporter Activity Using a Porphyrin Solubility Switch. Chem. Biol. 21, 422–429 (2014).
Shapiro*, M. G., Westmeyer*, G. G., Romero, P. A., Szablowski, J. O., Kuster, B., Shah, A., Otey, C. R., Langer, R., Arnold, F. H., and Jasanoff, A. (2010) "Directed evolution of a magnetic resonance imaging contrast agent for noninvasive imaging of dopamine", Nat Biotechnol 28: 264-270; * contributed equally
Westmeyer, G. G., Durocher, Y., and Jasanoff, A. (2010) "A secreted enzyme reporter system for MRI", Angew Chem Int Ed Engl 49: 3909-391
Westmeyer, G. G., and Jasanoff, A. (2007) "Genetically controlled MRI contrast mechanisms and their prospects in systems neuroscience research", Magn Reson Imaging 25: 1004-1010
Shapiro, M. G., Atanasijevic, T., Faas, H., Westmeyer, G. G., and Jasanoff, A. (2006) "Dynamic imaging with MRI contrast agents: quantitative considerations", Magn Reson Imaging 24: 449-462
Prof. Schilling conducts research in the field of preclinical molecular imaging. His research focusses on the development of novel methods in the area of magnetic resonance imaging (MRI). Together with his group he characterizes and validates imaging biomarkers. Interdisciplinarity is an essential characteristic of this area of research which combines the development of physical methods, the chemical characterization and synthesis of molecular sensors, as well as the investigation of biological and medical research questions.
Düwel S, Hundshammer C, Gersch M, Feuerecker B, Steiger K, Buck A, Walch A, Haase A, Glaser SJ, Schwaiger M, Schilling F: „Imaging of pH in vivo using hyperpolarized 13C-labeled zymonic acid“. Nature Communications. 2017; 8: 15126.
Schilling F, Ros S, Hu De-En, D’Santos P, McGuire S, Mannion E, Neves AA, Brindle K: „MRI measurements of reporter-mediated increases in transmembrane water exchange enable detection of a gene reporter“. Nature Biotechnology. 2017; 35: 75-80.
Hundshammer C, Düwel S, Köcher S, Gersch M, Feuerecker B, Scheurer C, Haase A, Glaser SJ, Schwaiger M, Schilling F: „Deuteration of hyperpolarized 13C-labelled zymonic acid enables sensitivity-enhanced dynamic MRI of pH“. ChemPhysChem. 2017; 18(18): 2422:2425.
Schilling F, Warner LR, Gershenzon NI, Skinner TE, Sattler M, Glaser SJ: „Next Generation Heteronuclear Decoupling for High Field Biomolecular NMR“. Angewandte Chemie International Edition. 2014; 126(17): 4564-4568.
Schilling F, Düwel S, Köllisch U, Durst M, Schulte RF, Glaser SJ, Haase A, Otto AM, Menzel MI: „Diffusion of hyperpolarized 13C metabolites in tumor cells spheroids using real-time NMR spectroscopy“. NMR in Biomedicine. 2013; 26(5): 557-568.
Infection and Immunology
The major focus of the Busch laboratory is to visualize and track antigen-specific T cell populations during in vivo antigen challenge to increase our understanding of how T cell responses are regulated in vivo and how protective and long lasting immunity is established. This knowledge is of special interest for adoptive immunotherapy, diagnostic monitoring of T cell mediated immunity, and the development of new vaccination strategies.
Antigen-specific T cell responses are of major importance in the control of infection and the development of protective immunity. T cells can also mediate anti-tumor effects and, in the case of autoimmune syndromes, can contribute to the development and pathology of disease.
Over the last few decades, numerous epitopes recognized by antigen-specific T cells have been identified, and general features of T cell responses revealed. Due to the difficulty of identifying antigen-specific T cells directly ex vivo, however, many basic questions regarding the in vivo regulation of antigen-specific T cell responses and the generation of protective immunity are still unsolved. Using new immunological methods, especially MHC multimer technologies, we are now able to directly identify and isolate T cells depending on their antigen specificity.
The goal of this lab is to further develop these new advances in immunological techniques, to investigate antigen-specific T cell responses in an animal model and to test direct clinical applications of the technology.
Buchholz, V. R., Flossdorf, M., Hensel, I., Kretschmer, L., Weissbrich, B., Graf, P., Verschoor, A., Schiemann, M., Hofer, T., and Busch, D. H. (2013) Disparate Individual Fates Compose Robust CD8+ T Cell Immunity, Science 340(6132):630-5.
Nauerth, M., Weißbrich, B., Knall, R., Franz, T., Dössinger, G., Bet, J., Paszkiewicz, P.J., Pfeifer, L., Bunse, M., Uckert, W., Holtappels, R., Gillert-Marien, D., Neuenhahn, M., Krackhardt, A., Reddehase, M. J., Riddell, S. R., and Busch, D. H. (2013) TCR-ligand koff-rate predicts protective capacity of antigen-specific CD8+ T cells for adoptive transfer. Science Translational Medicine 5(192):192ra87.
Busch D.H., I.M. Pilip, S. Vijh, and Pamer E.G. (1998) Coordinate regulation of complex T cell populations responding to bacterial infection. Immunity 8: 353-362.
Knabel M, Franz TJ, Schiemann M, Wulf A, Villmow B, Schmidt B., Bernhard H., Wagner H, and Busch DH (2002). Reversible MHC multimer staining for functional isolation of T cell populations and effective adoptive transfer. Nature Medicine, 8; 631-637.
Huster K.M., Busch V., Schiemann M., Linkemann K., Kerksiek K.M., Wagner H. and Busch D.H. (2004). Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets. PNAS 101(15):5610-5.
Neuenhahn M., Kerksiek K.M., Nauerth M., Suhre M.H., Schiemann M., Gebhardt F.E., Stemberger C., Panthel K., Schröder S., Chakraborty T., Jung S., Hochrein H., Rüssmann H., Brocker T. , and Busch D.H. (2006) CD8alpha-positive dendritic cells are required for efficient entry of Listeria monocytogenes into the spleen. Immunity Oct;25(4):619-30.
Stemberger C., Huster H., Koffler M., Anderl F., Schiemann M., Wagner H., and Busch D.H. (2007) A single naive CD8+ T cell precursor can develop into diverse effector and memory subsets. Immunity. 2007 Dec;27(6):985-97.
Our group is interested in studying the molecular mechanisms determining local regulation of immune responses in tissues, in particular in the liver. We employ modern cutting edge technologies to characterize the interaction of immune cells with tissue cells and how this shapes the quality of immune responses in the context of pathogen infection, metabolic challenges and chronic inflammation leading to tumor development. Understanding the principles of local regulation of immune responses is key to understand the molecular pathophysiology of organ-specific diseases. Such knowledge forms the basis for developing next-generation immune therapies based on novel concepts for therapeutic vaccination and for improving immune diagnostics through quantitative measurement of immune responses in tissues.
We are focusing on the regulation of immune responses in the liver and how the mechanistic understanding of the local balance between immunogenic and tolerogenic signals can be employed to achieve clearance of chronic viral infections and to eradicate tumor cells from the liver. We are further exploring the role of the liver in systemic immunity and how T cells primed in the liver contribute to protective immunity against pathogen infection.
We invite you to explore our homepage for further information.
Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 2010, 10(11): 753-766.
Protzer U, Maini MK, Knolle PA. Living in the liver: hepatic infections. Nat Rev Immunol 2012, 12(3): 201-213.
Wohlleber D, Kashkar H, Gartner K, Frings MK, Odenthal M, Hegenbarth S, Limmer A, Cederbrant K, Heikenwalder M, Pasparakis M, Protzer U, Dienes HP, Kurts C, Kronke M, Knolle PA. TNF-Induced Target Cell Killing by CTL Activated through Cross-Presentation. Cell Reports 2012, 2(3): 478-487.
Huang LR, Wohlleber D, Reisinger F, Jenne CN, Cheng RL, Abdullah Z, Schildberg FA, Odenthal M, Dienes HP, van Rooijen N, Schmitt E, Garbi N, Croft M, Kurts C, Kubes P, Protzer U, Heikenwalder M, Knolle PA. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection. Nat Immunol 2013, 14(6): 574-583.
Böttcher JP, Schanz O, Wohlleber D, Abdullah Z, Debey-Pascher S, Staratschek-Jox A, Hochst B, Hegenbarth S, Grell J, Limmer A, Atreya I, Neurath MF, Busch DH, Schmitt E, van Endert P, Kolanus W, Kurts C, Schultze JL, Diehl L, Knolle PA. Liver-Primed Memory T Cells Generated under Noninflammatory Conditions Provide Anti-infectious Immunity. Cell Reports 2013, 3(3): 779-795.
Böttcher JP, Schanz O, Garbers C, Zaremba A, Hegenbarth S, Kurts C, Beyer M, Schultze JL, Kastenmuller W, Rose-John S, Knolle PA. IL-6 trans-Signaling-Dependent Rapid Development of Cytotoxic CD8(+) T Cell Function. Cell Reports 2014, 8(5): 1318-1327.
Wolf MJ, Adili A, Piotrowitz K, Abdullah Z, Unger K, Karin M, Kopf M, Knolle P, Weber A, Heikenwalder M. Metabolic Activation of Intrahepatic CD8(+) T Cells and NKT Cells Causes Nonalcoholic Steatohepatitis and Liver Cancer via Cross-Talk with Hepatocytes. Cancer Cell 2014, 26(4): 549-564.
In our research, we try to understand why autoreactive T cell responses can result in organ specific autoimmunity like multiple sclerosis or neuromyelitis optica. Autoreactive T cells occur in any "normal" T cell repertoire, but are kept in check by mechanisms of dominant tolerance like for example regulatory T cells (Tregs). We are interested in identifying molecular switches and cytokine networks that break immunological tolerance in the peripheral immune compartment and direct the fate of an autoreactive T cell to become autopathogenic. Validation of molecular targets is performed in animal models of multiple sclerosis like for example experimental autoimmune encephalomyelits.
Garg G, Muschaweckh A, Moreno H, Vasanthakumar A, Floess S, Lepennetier G, Oellinger R, Zhan Y, Regen T, Hiltensperger M, Peter C, Aly L, Knier B, Palam LR, Kapur R, Kaplan MH, Waisman A, Rad R, Schotta G, Huehn J, Kallies A & Korn T. (2019) Blimp1 prevents methylation of Foxp3 and loss of regulatory T cell identity at sites of inflammation. Cell reports, 26 (7): 1854-1868.e5.
Knier B, Hiltensperger M, Sie C, Aly L, Lepennetier G, Engleitner T, Garg G, Muschaweckh A, Mitsdörffer M, Koedel U, Höchst B, Knolle P, Gunzer M, Hemmer B, Rad R, Merkler D & Korn T. (2018) Myeloid-derived suppressor cells control B cells within the central nervous system during autoimmunity. Nature Immunology, 19 (12): 1341-1351.
Heink S, Yogev N, Garbers C, Herwerth M, Aly L, Gasperi C, Husterer V, Croxford AL, Möller-Hackbarth K, Bartsch HS, Sotlar K, Krebs S, Regen T, Blum H, Hemmer B, Misgeld T, Wunderlich TF, Hidalgo J, Oukka M, Rose-John S, Schmidt-Supprian M, Waisman A & Korn T. (2017) Dendritic cells are non-redundant sources of IL-6 for the priming of pathogenic Th17 cells due to a novel mode of IL-6 signaling. Nature Immunology, 18: 74-85.
Petermann F, Rothhammer V, Claussen MC, Haas JD, Riol-Blanco L, Heink S, Prinz I, Hemmer B, Kuchroo VK, Oukka M & Korn T. (2010) γδ T cells enhance autoimmunity by restraining Treg responses via an IL-23 dependent mechanism. Immunity, 33: 351-363.
Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, Oukka M & Kuchroo VK. (2007) IL-21 initiates an alternative pathway
Korn T, Reddy J, Gao W, Bettelli E, Awasthi A, Petersen TR, Bäckström BT, Sobel RA, Wucherpfennig KW, Strom TB, Oukka M & Kuchroo VK. (2007) Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nature Medicine, 13: 423-431.
Our main scientific interests are to better understand the interaction of hepatitis B virus (HBV) with its host and to develop new (gene and immune) therapeutic strategies to treat chronic viral hepatitis and hepatocellular carcinoma.
The majority of the team is currently focusing on how HBV is controlled by cellular defense mechanisms and by the systemic immune response, and how HBV manages to escape this immune control. To be able to study this, we have developed new animal and cell culture models of HBV infection and new molecular diagnostic assays. We have established two HBV-transgenic mouse lines as models for a vertical transmission, and have developed a mouse model of self-limited hepatitis B.
Based on an improved basic understanding of the control of HBV infection we are developing new treatment strategies to treat chronic viral hepatitis. For example, we study the molecular mechanisms of antiviral effects of cytokines and other immune mediators, and investigate the possibility of a therapeutic cytokine gene transfer. Since we are convinced that immune tolerance needs to be overcome to cure chronic infection, we also follow strategies of therapeutic vaccination and try to redirect T cells to infected cells by generating recombinant T cell receptors. By grafting them onto primary T cells we follow a novel strategy in the treatment of infectious diseases.
Other topics of our group are metabolic alterations caused by hepatitis C virus, T cell therapy of HCV and hepatocellular cacinoma and developing new vectors systems for a liver directed gene transfer. As the first group worldwide, we managed to generate HBV based viral vectors. Recently, we successfully used HBV based vectors in a preclinical study in HCV infected chimpanzees.
Hösel M, Quasdorff M, Webb D, Zedler U, Esser K, Arzberger S, Wiegmann K, Kirschning CJ, Langenkamp A, Rose-John S and Protzer U. Not interferon, but IL-6 controls early gene expression in Hepatitis B virus (HBV) infection. Hepatology 2009, 50:1773-1782.
Bohne F, Chmielewski M, Ebert G, Wiegmann K, Kürschner T, Schulze A, Urban S, Krönke M, Abken H, Protzer U. T cells Redirected Against Hepatitis B Virus Surface Proteins Eliminate Infected Hepatocytes. Gastroenterology 2008, 134: 239-47.
Quasdorff M, Hösel M, Odenthal M, Zedler U, Bohne F, Gripon P, Dienes HP, Stippel D, Goeser T, Protzer U. A concerted action of HNF1 a and HNF4a links hepatitis B virus replication to hepatocyte differentiation. Cellular Micobiology 2008, 10:1478-1490.
Protzer U, Seyfried S, Quasdorff M, Sass G, Svorcova M, Webb D, Bohne F, Hösel M, Schirmacher P, Tiegs G.
Antiviral activity and hepatoprotection by heme oxygenase-1 in hepatitis B virus infection. Gastroenterology 2007, 133: 1156-65.
Untergasser A, Zedler U, Langenkamp A, Hösel M, Quasdorff M, Esser K, Tapperzhofen B, Kolanus W and Protzer U. Dendritic cells take up viral antigens but do not support the early steps of hepatitis B virus infection. Hepatology 2006, 43: 539-547.
Untergasser A & Protzer U. Hepatitis B virus vectors allow elimination of viral gene expression and insertion of foreign promoters. Human Gene Therapy 2004, 15: 203-210.
Sprinzl M, Oberwinkler H, Schaller H, Protzer U.
Hepatitis B virus genome transfer with adenoviral vectors into cultured cells and mice: crossing the species barrier Journal of Virology 2001, 75: 5108-5118.
U. Klöcker, U. Schultz, H. Schaller, U. Protzer.
Liver macrophages release mediators after endotoxin stimulation that inhibit an early step in hepadnavirus replication. Journal of Virology 2000, 74 (12): 5525-5533.
Protzer U, Nassal M, Chiang PW, Kirschfink M, Schaller H. Interferon gene transfer by a novel hepatitis B virus vector efficiently suppresses wildtype-virus infection. PNAS 1999, 96: 10818-10823.
Our Laboratory is interested in the molecular mechanisms of immune cell activation and in the pathogenesis of cancer. Using a wide variety of molecular, cellular and in vivo techniques we try to understand how the innate immune system detects microbial or endogenous danger and how subsequent intracellular signals drive inflammatory responses and host defense. In other projects, we are dissecting pathomechanisms of leukemia and lymphoma development and build novel models for these diseases. We hope that our work will contribute to the development of novel diagnostics and therapeutics for immune-mediated diseases and cancer.
Rosenbaum, M., Gewies, A., Pechloff, K., Heuser, C., Engleitner, T., Gehring, T., Hartjes, L., Krebs, S., Krappmann, D., Kriegsmann, M., Weichert, W., Rad, R., Kurts, C., Ruland, J. (2019). Bcl10-controlled Malt1 paracaspase activity is key for the immune suppressive function of regulatory T cells. Nat Commun 10, 2352.
Wartewig, T., Kurgyis, Z., Keppler, S., Pechloff, K., Hameister, E., Ollinger, R., Maresch, R., Buch, T., Steiger, K., Winter, C., Rad, R., Ruland, J. (2017). PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 552, 121-125.
Knies, N., Alankus, B., Weilemann, A., Tzankov, A., Brunner, K., Ruff, T., Kremer, M., Keller, U.B., Lenz, G., Ruland, J. (2015). Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-kappaB and JNK activation. Proc Natl Acad Sci U S A 112, E7230-8.
Roth, S., Rottach, A., Lotz-Havla, A.S., Laux, V., Muschaweckh, A., Gersting, S.W., Muntau, A.C., Hopfner, K.P., Jin, L., Vanness, K., Petrini, J.H., Drexler, I., Leonhardt, H., Ruland, J. (2014). Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1beta production. Nat Immunol 15, 538-45.
Neumann, K., Castineiras-Vilarino, M., Hockendorf, U., Hannesschlager, N., Lemeer, S., Kupka, D., Meyermann, S., Lech, M., Anders, H.J., Kuster, B., Busch, D.H., Gewies, A., Naumann, R., Gross, O., Ruland, J. (2014). Clec12a is an inhibitory receptor for uric acid crystals that regulates inflammation in response to cell death. Immunity 40, 389-99.
Strasser, D., Neumann, K., Bergmann, H., Marakalala, J.M., Guler, R., Rojowska, A., Hopfner, K., Brombacher, F., Urlaub, H., Baier, G., Brown, G. Leitges, M., and Ruland, J. (2012) Syk-coupled C-type lectin receptors engage PKCdelta to elicit Card9 mediated innate immunity. Immunity 36, 32-42
Environmental disease such as COVID19 or allergies are a major burden for our societies. They challenge the epithelial surfaces in an interplay with the immune system. Allergy is among the most frequent disease world wide and is further increasing in prevalence and will further aggravate with climate changes. Key aim is to understand natural tolerance mechanisms as well as therapeutic re-induction by treatment, convalescence or naturally remission. To prevent pandemics and epidemics in the future the ZAUM is monitoring the the environment and was able to install an automatic pollen measurement network in Bavaria. For COVID19 and other airway diseases we are exploring non-invasive diagnosis option using biomarker that are identified in our basic research activities. Also for skin barriers dramatic progress could be generated and novel diagnostic approaches are developing out of basic research based on human biobank samples.
Being a hybrid institute of TUM and Helmholtz Society, the institute takes advantage of cutting edge technologies as well as the strength of an university clinic. The institute offers a unique range of expertise from genetics over omics to bedside that has previously promoted careers with international recognition. ERC and EU, BMBF and DFG grants are lead by the team. ZAUM PIs are also member of several SFB/TRs and are also member of the German Center of Lung Research (DZL), and generated over the last 5 years more than 15 million € research funding. Graduates from ZAUM get usually employment opportunities from all over the world due to the outstanding publication record, 4 Profs were promoter from ZAUM alumni.
de Los Reyes Jimenez, M. et al. An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products. Sci Transl Med 12, (2020).
Zissler, U. M. et al. Early IL-10 producing B-cells and coinciding Th/Tr17 shifts during three year grass-pollen AIT. EBioMedicine 36, 475-488, (2018).
Oteros, J. et al. Artemisia pollen is the main vector for airborne endotoxin. J Allergy Clin Immunol 143, 369-377 e365, (2019).
Garzorz-Stark, N. et al. Toll-like receptor 7/8 agonists stimulate plasmacytoid dendritic cells to initiate TH17-deviated acute contact dermatitis in human subjects. J Allergy Clin Immunol 141, 1320-1333 e1311, (2018).
Xie, K. et al. Every-other-day feeding extends lifespan but fails to delay many symptoms of aging in mice. Nat Commun 8, 155, (2017).
Dietz, K. et al. Age dictates a steroid-resistant cascade of Wnt5a, transglutaminase 2, and leukotrienes in inflamed airways. J Allergy Clin Immunol 139, 1343-1354 e1346, (2017).
Krause, L. et al. A computational model to predict severity of atopic eczema from 30 serum proteins. J Allergy Clin Immunol 138, 1207-1210, (2016).
Chaker, A. M. et al. Short-term subcutaneous grass pollen immunotherapy under the umbrella of anti-IL-4: A randomized controlled trial. J Allergy Clin Immunol 137, 452-461 e459, doi:10.1016/j.jaci.2015.08.046 (2016).
Quaranta, M. et al. Intraindividual genome expression analysis reveals a specific molecular signature of psoriasis and eczema. Sci Transl Med 6, 244ra290, (2014).
Pennino, D. et al. IL-22 suppresses IFN-gamma-mediated lung inflammation in asthmatic patients. J Allergy Clin Immunol 131, 562-570, doi:10.1016/j.jaci.2012.09.036 (2013).
Eyerich, S. et al. Mutual antagonism of T cells causing psoriasis and atopic eczema. N Engl J Med 365, 231-238, (2011).
Adrenergic signaling in the heart:
Beta-adrenergic receptors are a subclass of G protein-coupled receptors which play a crucial role in the neurohormonal regulation of cardiovascular functions. Activation of these receptors is the strongest mechanism to increase cardiac frequency and contractility. However, sustained activation of b-adrenergic receptors contributes to the development of cardiac disease. We currently study b-adrenergic receptor signaling, search for novel downstream targets and study the impact of receptor polymorphisms on ligand-induced conformational changes of the receptor protein.
Role of microRNAs in cardiac health and disease:
MicroRNAs control diverse biological processes including major signaling pathways by regulating the expression of complementary target mRNAs. Although MicroRNAs were recently implicated in the regulation of diverse cardiac functions in a series of elegant genetic studies, detailed molecular mechanisms for microRNAs in disease pathways in vivo are poorly understood. We have identified several candidate microRNAs, which are severely deregulated in cardiac disease and established techniques for detecting, quantifying and manipulating microRNA expression.
Another research focus at the Institute of Pharmacology and Toxicology is the role of the ubiquitin-proteasome system. The laboratory of Dr. Antonio Sarikas uses interdisciplinary approaches that include modern methods of molecular biology, protein biochemistry and mouse genetics to study the regulation of signaling pathways by the ubiquitin-proteasome system. Please also see www.sarikaslab.de.
Görlach A, Lee P, Roesler J, Hopkins PJ, Christensen B, Green ED, Chanock SJ, Curnutte JT: "A p47-phox pseudogene carries the most common mutation causing p47-phox- deficient chronic granulomatous disease". J Clin Invest. 1997;100(8): 1907
Görlach A, Brandes RP, Nguyen K, Amidi M, Busse R: "A gp91phox containing NADPH oxidase selectively expressed in endothelial cells is a major source of oxygen radical generation in the arterial wall". Circ Res. 2000; 87 (1): 26-32.
Görlach A, Diebold I, Schini-Kerth VB, Berchner-Pfannschmidt U, Roth U, Brandes RP, Kietzmann T, Busse R: "Thrombin activates the HIF-1 signaling pathway in vascular smooth muscle cells. Role of the p22phox-containing NADPH oxidase".
Circ Res. 2001; 89(1):47-54.
BelAiba RS, Djordjevic T, Bonello S, Lang F, Hess J, Görlach A: "The serum- and glucocorticoid-regulated kinase Sgk-1 promotes redox-sensitive upregulation of tissue factor by thrombin". Circ Res. 2006; 98 (6): 828-836.
Diebold I, Djordjevic T, Petry A, Hatzelmann A, Tenor H, Hess J, Görlach A: "Phosphodiesterase 2 Mediates Redox-Sensitive Endothelial Cell Proliferation and Angiogenesis by Thrombin via Rac1 and NADPH Oxidase 2".
Circ Res. 2009; 104(10):1169-77.
Interventional cardiology; Clinical trials, incl. quantitative coronary angiography, optical coherence tomography; Genetic analysis; Prognostic biomarker analysis:
- Stent thrombosis
- Stent restenosis
- Improvement of stent technology, development and testing of drug-eluting stents
- periinterventional pharmacotherapy
- clinical relevance of platelet function tests
- Treatment strategies of acute coronary syndromes
- influence of genetic factors on outcome after PCI
- systematic review of randomized trials
Schomig A, Neumann FJ, Kastrati A, Schuhlen H, Blasini R, Hadamitzky M, Walter H, Zitzmann-Roth EM, Richardt G, Alt E, Schmitt C, Ulm K. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996; 334(17):1084-1089.
Schomig A, Kastrati A, Dirschinger J, Mehilli J, Schricke U, Pache J, Martinoff S, Neumann FJ, Schwaiger M. Coronary stenting plus platelet glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator in acute myocardial infarction. Stent versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction Study Investigators. N Engl J Med 2000; 343(6):385-391.
Kastrati A, Mehilli J, Schuhlen H, Dirschinger J, Dotzer F, ten Berg JM, Neumann FJ, Bollwein H, Volmer C, Gawaz M, Berger PB, Schomig A. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004; 350(3):232-238.
Dibra A, Kastrati A, Mehilli J, Pache J, Schuhlen H, von Beckerath N, Ulm K, Wessely R, Dirschinger J, Schomig A. Paclitaxel-eluting or sirolimus-eluting stents to prevent restenosis in diabetic patients. N Engl J Med 2005; 353(7):663-670.
Kastrati A, Mehilli J, Pache J, Kaiser C, Valgimigli M, Kelbaek H, Menichelli M, Sabate M, Suttorp MJ, Baumgart D, Seyfarth M, Pfisterer ME, Schomig A. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007; 356(10):1030-1039.
Kastrati A, Neumann FJ, Mehilli J, Byrne RA, Iijima R, Buttner HJ, Khattab AA, Schulz S, Blankenship JC, Pache J, Minners J, Seyfarth M, Graf I, Skelding KA, Dirschinger J, Richardt G, Berger PB, Schomig A. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008; 359(7):688-696.
Kastrati A, Ndrepepa G. Cangrelor -- a champion lost in translation? N Engl J Med 2009; 361(24):2382-2384.
An urgent need in cardiovascular medicine is to develop novel therapeutic tools and approaches to restore proper function of diseased hearts and to regenerate cardiac muscle after injury. Regenerative therapies, either by transplantation of stem cells or stem cell-derived differentiated cells into the defective organ or by promoting endogenous regenerative processes, are an important goal of cardiovascular research. In order to translate successfully these concepts into patient care, several fundamental research questions have to be answered. One core activity of this group is to address such questions with state-of-the-art methods. Among others, these techniuqes are applicated: generation, culture and differentiation of human pluripotent stem cells; genetic modification (CRISPR/Cas System); optical physiological characterization of cardiomyocytes (Calcium imaging, membrane potential imaging, second messenger imaging); 3D culture of iPS-derived cardiomyocytes; gene expression analysis (RNAseq, single-cell RNAseq); molecular cloning and cell injection into murine embryos.