The central nervous system (CNS) is our most complex organ system. Despite decades of intense research, many fundamental processes and diseases are still not fully understood. While a large body of literature exists regarding the role of chemical signalling in regulating CNS function, only recently groups of several members in this consortium, and a few other groups worldwide, have discovered an important contribution of mechanical stimuli. The proposed CRC ‘EBM’ will synergise the expertise of engineers, physicists, biologists, medical researchers, and clinicians in Erlangen to explore mechanics as an important yet missing puzzle piece in our understanding of CNS development, homeostasis, and pathology. Our strongly multidisciplinary team with unique expertise in CNS mechanics will integrate advanced in vivo, in vitro, and in silico techniques across time (development, ageing, injury/disease) and length (cell, tissue, organ) scales to uncover how mechanical forces and mechanical cell and tissue properties, such as stiffness and viscosity, affect CNS function. We will especially focus on (A) cerebral, (B) spinal, and (C) cellular mechanics. In vivo and in vitro studies will provide a basic understanding of mechanics-regulated biological and biomedical processes in different regions of the CNS. In addition, they will help identify key mechano-chemical factors for inclusion in in silico models and provide data for model calibration and validation. In silico models, in turn, will allow for data transfer across species and scales. They will additionally enable us to optimise process parameters for in vitro engineered brain tissue and in vivo mechanical stimulation, and, eventually, pave the way for personalised clinical predictions. In summary, we will exploit mechanics-based approaches to advance our understanding of CNS function and to provide the foundation for future improvement of diagnosis and treatment of neurological disorders.
Contact: Prof. Dr. med. Dr. Dr. h.c. Friedrich Paulsen, Institut of Anatomy
The CRC “Empathokinaesthetic Sensor Technology” (EmpkinS) will investigate novel radar, wireless, depth camera, and photonics based sensor technologies as well as body function models and algorithms. The primary objective of EmpkinS is to capture human motion parameters remotely with wave-based sensors to enable the identification and analysis of physiological and behavioural states and body functions. To this end, EmpkinS aims to develop sensor technologies and facilitate the collection of motion data for the human body. Based on this data of hitherto unknown quantity and quality, EmpkinS will lead to unprecedented new insights regarding biomechanical, medical, and psychophysiological body function models and mechanisms of action as well as their interdependencies. The main focus of EmpkinS is on capturing human motion parameters at the macroscopic level (the human body or segments thereof and the cardiopulmonary function) and at the microscopic level (facial expressions and fasciculations). The acquired data are captured remotely in a minimally disturbing and non-invasive manner and with very high resolution. The physiological and behavioural states underlying the motion pattern are then reconstructed algorithmically from this data, using biomechanical, neuromotor, and psychomotor body function models. The sensors, body function models, and the inversion of mechanisms of action establish a link between the internal biomedical body layers and the outer biomedical technology layers. Research into this link is highly innovative, extraordinarily complex, and many of its facets have not been investigated so far. To address the numerous and multifaceted research challenges, the EmpkinS CRC is designed as an interdisciplinary research programme. The research programme is coherently aligned along the sensor chain from the primary sensor technology (Research Area A) over signal and data processing (Research Areas B and C) and the associated modelling of the internal body functions and processes (Research Areas C and D) to the psychological and medical interpretation of the sensor data (Research Area D). Ethics research (Research Area E) is an integral part of the research programme to ensure responsible research and ethical use of EmpkinS technology. The proposed twelve-year EmpkinS research programme will develop novel methodologies and technologies that will generate cutting-edge knowledge to link biomedical processes inside the human body with the information captured outside the body by wireless and microwave sensor technology. With this quantum leap in medical technology, EmpkinS will pave the way for completely new “digital”, patient-centred diagnosis and therapeutic options in medicine and psychology. Medical technology is a research focus with flagship character in the greater Erlangen-Nürnberg area. This outstanding background along with the extensive preparatory work of the involved researchers form the basis and backbone of EmpkinS.
Contact: Prof. Dr. Björn Eskofier, Lehrstuhl für Maschinelles Lernen und Datenanalytik
“Cellular and Systems Control of Autoimmune Disease” (CASCAID) is a pioneering research programme dedicated to developing strategies for sustained drug-free remission in autoimmune and chronic inflammatory diseases, with the ultimate goal of finding a way to cure these diseases. Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease present a significant clinical challenge due to their chronic, non-resolving nature that necessitates lifelong immunosuppression. These conditions follow a characteristic pattern of repeated inflammatory flares and relapses, leading to the accrual of tissue damage and progressive organ dysfunction. Current treatment strategies, such as inhibitors of inflammatory cytokines TNFα (used in arthritis and inflammatory bowel disease), type 1 interferon (used in systemic lupus erythematosus) or interleukin-23 (IL-23) (used in inflammatory bowel disease) reduce inflammation but all fail to achieve sustained disease eradication. This therapeutic limitation suggests the existence of dysregulated immune cell networks deeply embedded within the affected tissues that maintain a persistent pro-inflammatory state and limit the success to induce stable-drug-free remission. CASCAID aims to identify and characterise these dysregulated networks by building on (i) the strength of the consortium in clinical immunology and (ii) the development of new diagnostic and therapeutic methodologies in autoimmune diseases. Specifically, at its core, CASCAID will bridge translational preclinical and clinical research by leveraging molecularly characterised large patient cohorts (arthritis, lupus erythematosus, and inflammatory bowel disease), human tissue samples (from joint synovium, lymph nodes and intestinal mucosa) and cutting-edge tissue profiling approaches (tissue CyTOF, spatial transcriptomics and multi-scale tissue microscopy). Within the theoretical framework of CASCAID, consortium members have already successfully developed novel treatment strategies in each disease area, including T cell engagers for rheumatoid arthritis, CD19 CAR T cells for lupus erythematosus, and regulatory T cells for inflammatory bowel disease. These treatments disrupt pathological immune networks and push therapeutic limits towards drug-free remission. By studying these interventions, CASCAID will elucidate the cellular and systems-level mechanisms in the tissues that control sustained drug-free remission, potentially transforming our approach to autoimmune disease management.
Contact: Prof. Dr. Georg Schett, Department of Medicine 3 – Rheumatology and Immunology
Allogeneic hematopoietic stem cell transplantation (ASCT) is a curative treatment option for patients with high-risk leukemia and lymphoma and for certain inherited or acquired hematopoietic deficiencies. Around half a million transplantations have been performed to date and approximately 42 million voluntary stem cell donors are currently registered world-wide. The curative potential of ASCT is based on the replacement of the patient´s hematopoiesis by hematopoietic stem cells derived from a healthy donor and the immunologic eradication of residual patient hematopoietic cells by co-transplanted lymphocytes. This graft-versus-hematopoiesis reaction is mainly mediated by alloreactive donor T cells that also attack malignant hematopoietic cells, thereby evoking potent graft-versus-leukemia / lymphoma (GvL) effects. Although ASCT offers a unique chance to rescue patients with otherwise incurable hematologic malignancies, still around one quarter of ASCT recipients develop disease relapse after ASCT. Thus, there is an urgent need to better understand and ultimately strengthen GvL responses. Yet, donor T cells also attack solid organs in about half of patients, a transplant complication called graft-versus-host disease (GvHD) that can become life-threatening and in its acute form mainly affects skin, liver and gut. Therefore, it is the central goal of the TRR to elucidate the immunological mechanisms of GvL and GvHD responses to increase the efficacy of ASCT without increasing the risk for GvHD. To achieve this goal scientists of project area A analyze new molecular targets and cellular pathways (e.g. T cell receptor & chimeric antigen receptor transfer, T memory stem cells) to augment GvL responses and assess them in in vivo models. In project area B scientists examine basic pathomechanisms of GvH-reactivity and develop new strategies for the prevention and/or therapy of this transplant complication. Here, the specific modulation of T cell signal transduction pathways is explored, regulatory molecular and cellular networks within innate and adaptive immune compartments are examined as well as GvHD-promoting co-factors, such as inflammatory pathways and microbiome alterations. Strategies aimed to strengthen GvL effects are always tested for their influence on GvHD and vice versa. The most promising strategies evolving from these studies are and shall be tested in clinical trials. Several members of TRR are “clinician scientists” who continuously conduct first-in-man investigator-initiated clinical trials in the ASCT and cellular therapy field. Twenty-three trials are currently funded or applied for funding (from resources outside the TRR). Thus, TRR is strongly committed to bridge the gap between basic and translational immunology research in ASCT and cellular immunotherapy to achieve our fundamental mission: to improve the safety and efficacy of ASCT.
Contact: Prof. Dr. A. Mackensen, Department of Medicine 5 – Haematology and Oncology
The TRR is based on research into biofabrication and its systematic use with the long-term goal of producing functional tissue models. Biofabrication is defined as the use of automated 3D printing processes for the production of hierarchical cell-material constructs in a spatial arrangement, which should enable maturation into tissue models with functional properties. This offers the possibility of automated production of functional tissue models, which would be invaluable as a substitute for animal experiments, for pharmaceutical and cancer research and as a regenerative therapy option. The focus of the first funding period (FP1) of the TRR was on the development of materials and processes with a focus on the survival of cells in the printing process. In FP2, the focus shifted to the behavior of the cells in the printed biofabricates and the development of initial tissue models. With 163 publications in peer-reviewed scientific journals, the TRR was able to make a significant contribution to the research field in FP2. More than half of these studies are the result of cooperation between at least two subprojects, demonstrating the truly collaborative nature of the TRR consortium. This is complemented by 10 patent applications resulting from the network, an evolving spin-off initiative, and an EIC transition project. In line with the initial plan, in FP3 the consortium is focusing on research and further development of tissue models with biologically functional properties. To achieve this, the activities in the project areas of bioinks (A) and methods (B) are specifically geared towards the requirements of the projects in the area of biofabricated models (C). The TRR sites had already created a unique basis with the establishment of the first two Master’s degree courses and the first two professorships for biofabrication in Germany. During the TRR funding period, further structure-building measures were taken, such as the establishment of four additional professorships, the founding of the cross-faculty Institute for Functional Materials and Biofabrication (IFB) and the construction of the Center of Polymers for Life (CPL) research building in Würzburg, a unique integrative infrastructure for biofabrication research. Biofabrication is a growing field of research with great prospects for the future. Thus, also the BMBF is planning future funding initiatives for “Bioprinting as a key technology for the medicine of the future” (brochure October 2023). For the TRR, in addition to the follow-up activities resulting from the consortium itself, concrete future areas of application are models for infection research or the central nervous system, for which specialized CRCs exist in Würzburg and Erlangen. Taken together, for the TRR, the structural measures and the research work with the unique combination of fundamental understanding and successful aspects of translational research thus provide excellent prospects far beyond FP.
Contact: PD Dr. med. vet. Dr. habil. med. Annika Kengelbach-Weigand, Department of Plastic and Hand Surgery
Inflammatory bowel diseases (IBD, Crohn’s disease, ulcerative colitis) are characterized by destructive and progressive chronic inflammation of the digestive tract. To date there is no cure available for IBD patients and with the increasing incidence of IBD, there is an urgent clinical need for novel therapies. The lack of curative options stems from the fact, that the early causative events in the etiology of IBD are poorly understood. What is known is that a complex interplay between genetic predisposition, gut microbiota and environmental factors triggers a dysregulated intestinal immune response that initiates and perpetuates mucosal inflammation. Deciphering the molecular and cellular interactions of this interplay and their pathophysiological consequences are the core goals of the TRR 241. A better understanding of IBD mechanisms will create a rationale for future innovative therapeutic approaches. Over the past, researchers in the field of IBD have highlighted two important components in the pathophysiology of IBD, which have been mostly studied in an independent fashion: The epithelial barrier that shields the bowel wall against the intestinal microbiota, and the complex nature of a dense immune cell network and its mediators within the lamina propria. The TRR 241 connects these two components into a concept that highlights the role of immune-epithelial crosstalk in the pathogenesis of IBD and that understands the gut epithelium as an immunological rather than a physical barrier. Thus, the unifying aim of the TRR 241 consortium is to decipher the bidirectional signal exchange between the intestinal epithelium and the mucosal immune system. The TRR 241 hypothesizes that the nature and the spatiotemporal regulation of immune-epithelial communication determine the pathogenesis of IBD. The scientific program of the TRR 241 is classified into three established project areas: In Project Area A, researchers of TRR 241 study how specific cytokines and immune components, released during acute and chronic inflammation within the lamina propria, regulate intestinal barrier function. In Project Area B, involved researchers apply models of barrier dysfunction and antigen exposure to study the temporal and spatial characteristics of developing immune responses. Finally, Project Area C aims to develop and clinically evaluate innovative therapeutic and diagnostic approaches. Collectively, the TRR 241 is highly committed to identifying key mechanisms of immune-epithelial dysregulation and testing new therapeutic targets with the long-term goal of improving the therapy of IBD patients.
Contact: Prof. Dr. Christoph Becker, Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology
In Germany, more than 4 million patients live with the diagnosis “cancer”. For many of them local disease control could be achieved and they live under the Damocles’ sword of pending relapse, i.e. the threat
of death from metachronous metastasis. Late distant relapses, however, demonstrate that disseminated cancer cells (DCCs) survive long periods outside the primary tumour and retain the ability to grow and form a metastasis. But what are the mechanisms that are operative during clinical latency periods? What determines whether DCCs remain under control or start to form metastases? Which systemic or organ-specific
factors prevent or promote distant relapse after primary treatment and how could therapeutic intervention prevent metachronous metastasis best? The TRR 305 is focusing on these specific questions of the complex
metastatic cascade with the goal to pave the way for the development of a new generation of metastasis-preventive therapies. The research programme is structured into two key research areas that reflect the
main objectives. Research area A – Cancer cell adaptation to selection forces will focus on cell intrinsic properties functionally linked to the generation of metastasis. It will comprise a framework for the understanding of the sequence of mutational events and thereby define the evolutionary and molecular state of colonising DCCs upon which plasticity is generated. It will then address mechanisms of cancer cell plasticity directly, i.e. how it is generated and how it is regulated. It also includes a technical platform to measure responses of cancer cells to changing microenvironmental conditions and selection forces. Research area B – Immune and niche-dependent conditions of metastatic colonisation focuses on cancer cell interactions with the microenvironment at colony formation. These interactions can either be organ-independent and of general significance or organ-specific determining site-specific metastasis, reflecting the co-adaptation of invading DCCs and niche cells. Also, research area B comprises a technology development project for studying complex cellular interactions by novel in vitro assays. These two research areas built upon each other and thereby will provide ample opportunity and need for interaction and cooperation. Together, they will reciprocally inform
about the best and most promising preclinical implementation and enable critical evaluation of clinical targeting chances. These steps will be enabled and promoted by the central Z-platforms.
Contact: Prof. Dr. Thomas Brabletz, Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology
Inflammation is a key precipitator for local and systemic bone disease. Bone loss and fractures are highly prevalent in a wide range of chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and periodontitis. By exploiting technological and conceptual advances, DIONE aims to define novel pathways that control bone remodeling during inflammation. DIONE comprises three main research sections: (A) The characterization of systemic regulatory immune signals that determine the function of bone-resorbing and bone-forming cells. (B) The identification of microenvironmental factors that determine the bone resorptive niche. (C) The investigation of cell-intrinsic factors that regulate osteoclast function and metabolism and thereby contribute to bone loss. The three sections will be supported by a central clinical project, allowing fast translation of our research using the databases and bio-samples of Erlangen and Dresden. Moreover, an infrastructure project will manage the data of our research initiative and allow a FAIR handling as well as fast and secure transfer of the data between the participants to strengthen transparency and foster collaboration. This strategy will push innovation and create new insights into the mechanisms and therapeutic approaches to ameliorate inflammatory bone loss.
Contact: Prof. Dr. Aline Bozec, Department of Medicine 3 – Rheumatology and Immunology
In Germany, more than 5 million patients suffer from chronic kidney disease (CKD) – most of them without knowing it – and about 100,000 require renal replacement therapy in the form of dialysis or transplantation. CKD can result from systemic diseases such as diabetes mellitus, arterial hypertension, or immune disorders, as well as from primarily intrarenal causes such as primary glomerular disease, glomerular and interstitial inflammation, inherited tubular transport defects, or polycystic kidney disease. Regardless of which cell types are primarily affected, the tubular system and interstitial cells are critically involved in many of these disease processes and tubular atrophy and interstitial fibrosis are hallmarks of CKD progression. In its first funding period, the CRC 1350 investigated the diverse functions and interplay of tubular epithelia and interstitial cells. We have gained important insights into pathomechanisms in several monogenic diseases, identified genetic risk factors in multifactorial kidney diseases, studied function and malfunction of interstitial cells, interstitial inflammation and fibrosis, and investigated damage memory and the consequences of hypoxia. For example, a team of CRC researchers uncovered the importance of TMEM16A (Ano1) chloride channels for cyst growth, confirmed the mechanism in animal models, demonstrated the efficacy of inhibitors of these channels, and finally established an ex vivo model to test the effects in human cystic kidney tissue to develop strategies for treatment of polycystic kidney patients. For the next funding period, the overall goal is to further deepen our knowledge of the (patho ) physiology of the tubular system and the renal interstitium, with a focus on developing new diagnostic and therapeutic strategies. To achieve this ambitious goal, we will incorporate further signaling pathways, new state-of-the-art methods, innovative models and analysis strategies into our research concept. For this, the transformation of CRC 1350 into TRR 374 is an important prerequisite, as this is the best way to achieve the necessary development. The research team will be further strengthened by the inclusion of outstanding (clinician) scientists, translational research projects and advanced data analysis. As TRR 374, we are well-positioned to shape nephrology research and to train the renal researchers and clinicians of the future.
Contact: Prof. Dr. Mario Schiffer, Department of Medicine 4 – Nephrology and Hypertension
Colorectal carcinogenesis is a prime example illustrating that tumor evolution, beyond the presence of critical mutations in intestinal stem cells, heavily relies on the interaction between mutagenized epithelial cells and the tumor microenvironment (TME), which profoundly influences every stage of tumor development. Crucially, the bidirectional communication between tumor epithelia and the TME is essential not only for all phases of tumorigenesis but also plays a significant role in individual responses to cancer therapies. Yet, most current treatment protocols still focus on eliminating mutated tumor cells without accounting for the TME’s contributions. Improved combinatorial and multi-modal therapies could offer better outcomes, which are desperately needed given the disease’s dismal five-year survival rate of just 64%. To address this critical unmet need, we aim to form an interdisciplinary Collaborative Research Center/Transregio (TRR). Our goal is to develop a comprehensive understanding of the functional role of the colorectal TME in CRC biology and therapy response. Beyond its scientific objectives, the TRR aims to train the next generation of clinician-scientists, providing early-career researchers with the opportunity to establish long-term careers in colorectal cancer research in Germany, extending beyond the twelve years of funding. Our hypothesis is that a deep understanding of the cellular and molecular mechanisms within the TME will lead to novel translational strategies targeting the TME, enhancing current therapies and making immunotherapy viable for microsatellite-stable CRC. The infrastructure and conceptual foundation for this TRR have been laid by the previously funded RU 2438, which has established preclinical models (including animal models and patient-derived organoid systems) and technologies harmonized across all three applicant universities. Building on this success, the TRR has selected leading scientists with expertise in emerging research areas to lead projects in collaboration with translational and clinical CRC experts. The TRR aims to perform groundbreaking basic research that will enable evaluation in clinical studies associated with the consortium. The participating scientists have been selected from universities affiliated with the Oncology Centers of Excellence (Onkologische Spitzenzentren) supported by the Deutsche Krebshilfe, the German Cancer Consortium (DKTK), the Bavarian Center for Cancer Research (BZKF), and the recently expanded National Center for Tumor Diseases (NCT). By bringing together experts from these institutions in basic and translational CRC research, the TRR will establish a unique center of excellence for CRC research in Germany. Targeting the TME for CRC therapy is a timely and promising approach that holds the potential for innovative strategies to improve the outcomes of the many patients who are currently facing a poor prognosis.
Contact: Prof. Dr. Markus F. Neurath, Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology
In recent years, multiple lines of evidence have led to the new concept that perturbation ofneurodevelopmental processes constitutes an important determinant for the pathogenesis ofand vulnerability to adult-onset neuropsychiatric and neurodegenerative disorders. Thepathophysiological mechanisms by which disruption of neurodevelopmental processes resultsin disorders of the adult CNS remain largely unknown. The RTG 2162 bundles the expertiseof basic and clinical neuroscientists in the genetics, molecular, cellular, and systems biologyof neurodevelopment and the pathophysiology of neuropsychiatric and degenerative disordersto provide a unique and innovative research and training programme that addresses the following key questions: i) What is the overlap in pathophysiology and genetics between neurodevelopmental and adult-onset CNS disorders? ii) What is the function ofneuropsychiatric and -degenerative disease genes during development? iii) What is the impactof developmental processes on vulnerability to disease-precipitating insults in later life?Researchers apply a broad range of methods, spanning modelling of (patho)biologicalprocesses using small animal models and human pluripotent stem cell-derived models, andanalysis adopting state-of-the-art approaches in molecular, developmental & cell biology,biochemistry, genomics, imaging, electrophysiology and mechanobiology. The conceptual linkbetween research questions and the diversity of approaches offer many opportunities for livelyexchange and collaborations between researchers. A mentoring committee, whose membershold complementary expertise, accompanies researchers throughout their doctoral projects.The curriculum familiarizes the fellows with new scientific concepts, methods, and soft skillsand enables early exposure to the international science community. A key element of thetraining concept is the integrated education of PhD-, MD-doctoral fellows and physicianscientists,to expose fellows to the translational aspects of their research early in their career.In summary, the RTG 2162 will provide intensive training in an innovative field at the interfaceof basic and translational neuroscience. Scientifically, the RTG 2162 will generate new insightinto the impact of development on neuropsychiatric and -degenerative disorders, therebyfurthering our understanding of the etiology of neurological and mental diseases.
Contact: Prof. Dr. Dieter Chichung Lie, Institut of Anatomy
The goal of the proposed Research Training Group is to establish an internationally competitive research and training program to promote young scientists and medical students in the field of immunology. The analysis of defined molecular regulators using genome-wide transcriptome analysis, modern imaging techniques, transgenic mouse technologies and CRISPR-mediated genome editing will identify and characterize new fine-tuners of adaptive immune responses and immune memory. To reach our goal, we have recruited five female and 12 male researchers with an internationally recognized expertise in the field of adaptive immunity from eight institutes and clinical departments at the Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU). All researchers are supported by third-party funding and experienced in graduate training. We also offer an innovative training program for Dr. rer. nat. candidates with a master’s degree in life sciences. This program consists of a bi-weekly RTG Paul-Ehrlich-Club, research-specific as well as interdisciplinary hard skill and soft skill workshops, internal RTG research retreats and RTG network meetings, the RTG guest speaker series, and the RTG’s public relation program. Furthermore, we have developed a fast-track program that will lead six fellows with a bachelor’s degree to the Dr. rer. nat. degree without the need to obtain a master’s degree. During their one-year qualification phase, the fast-track candidates will be prepare for their dissertation phase and receive extensive training in molecular biology and immunology within the Master’s program “Integrated Immunology,” attend RTG-specific events, and participate in a research-oriented rotation in a laboratory outside of Germany. To motivate medical students for basic research, we will set up an innovative and structured 18-month-long doctoral program. Highlights of this program are an 8-month lab phase and a curriculum tailored to the educational needs of each medical student. A three-member thesis advisory committee will mentor all doctoral candidates through-out their entire thesis project. To internationally position our doctoral candidates, they will organize the 7th International RTG Symposium on “Regulators of Adaptive Immunity” and do research rotations in laboratories outside of Germany. We are convinced that our innovative training and research concept with hypothesis-driven projects will better prepare our doctoral candidates for a professional post-graduate career as an immunologist and help them to develop into critically thinking scientists, to complete their thesis in 3-4 years, and to build an international network.
Contact: Prof. Dr. Mario Zaiss, Department of Medicine 3 – Rheumatology and Immunology
In recent years, it has become clear that the tissue microenvironment, milieu factors and the cellular metabolism have a tremendous impact on the development and general function of immune cells. However, it is
still poorly understood, to which extent these parameters also govern the antimicrobial defense and the survival of microbial pathogens.The scientific basis of the proposed RTG is the hypothesis that the anti-infectious immune response and its evasion by microorganisms are strongly influenced by the tissue context, the micromilieu components and the metabolism at the site of infection, which we collectively term
“immunomicrotope”. Consequently, the overarching goal of our RTG proposal is to train a new generation of scientists, who in their thesis identify host- or microbe-derived factors that shape the microenvironment in the infected tissue and thereby regulate the function of immune cells and/or the persistence of non-viral infectious agents (bacteria, fungi, parasites). The two project areas (tissue microenvironment and milieu factors; metabolism of host immune cells and pathogens) are closely related and interconnected. They fit seamlessly into the research focus “Infectious Diseases and Immunology” at FAU and build on established infectious disease models, the availability of key technologies, and on an excellent infrastructure and scientific environment.The structured training program of the RTG will convey the necessary theoretical knowledge, specific technical capabilities and general research skills to the doctoral candidates in order to allow for an efficient analysis of the “immunomicrotope” and a successful thesis work. Among other components, it consists of seminars on good scientific and laboratory practice, courses on imaging, metabolomics and
bioinformatics, international laboratory exchanges, a doctoral candidates´ jour fixe, a guest seminar series, an annual retreat and a biennial international symposium. With the help of a thorough supervision strategy the RTG will promote and foster a professional and creative attitude amongst the doctoral candidates, characterized by enthusiasm for science, commitment to the project and the development of own scientific ideas and concepts. As a future perspective, we believe that the proposed RTG will be an ideal training platform of young investigators for (inter)national research institutions in the field of infectious disease immunology and molecular microbiology.
Contact: Prof. Dr. Christian Bogdan, Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene
Rheumatoid Arthritis (RA) is a severe chronic inflammatory disease that is characterized by an early breach in immune tolerance and persisting autoimmunity. The autoimmune response triggers the onset of a chronic arthritis affecting peripheral joints, which typically show synovial inflammation and destruction of articular cartilage and bone. Research in the field of RA has been traditionally focused on the understanding of the mechanisms underlying synovitis and joint destruction. These efforts resulted in the successful development of targeted immune modulatory drugs for the treatment of this disease. However, key questions about factors responsible for the breach in immune tolerance and the initial onset of disease remain unanswered. As a consequence, current therapies primarily aim to suppress the inflammatory response, rather than targeting autoimmunity, inducing tolerance or offering preventive strategies. Although usually effective in controlling disease activity to some extent, the established treatments do not tackle the underlying problem of autoimmunity and thus require a life-long treatment. Curative therapeutic concepts for RA patients are still out of reach. Within the Research Unit named PANDORA (Pathways triggering autoimmunity and defining onset of early rheumatoid arthritis), we bundle the expertise of internationally-renowned scientists and seek to unravel the mechanisms responsible for the early immune-pathogenesis of RA. By focusing on two key checkpoints – the loss of immune tolerance and the transition from autoimmunity to inflammation – we want to identify new concepts underlying the pathogenesis of early RA and thereby develop strategies for preventive and curative treatment approaches. Embedding this Research Unit into the research environment and infrastructure of the Friedrich Alexander University Erlangen-Nürnberg (FAU) and the University Hospital of Erlangen (UKER) offers the unique possibility of combining cutting edge techniques in immunology and molecular biology with preclinical disease models, modern imaging and well-characterized RA patient cohorts. Together with one ongoing and one additionally planned innovative clinical trial that seem to re-induce tolerance in RA, this concept provides the ground for a high level translational research program.
Contact: Prof. Dr. Mario Zaiss, Department of Medicine 3 – Rheumatology and Immunology
The gut-brain axis is a bidirectional communication system driven by neural, hormonal, metabolic, immunological, and microbial signals. Signaling events from the gut can modulate brain function and recent evidence suggests that a dysregulated gut-brain axis plays a pivotal role in linking gastrointestinal and neurological diseases. In this context, clinical data reveal that patients with Inflammatory Bowel Disease (IBD) are at higher risk of subsequently developing Parkinson’s disease (PD). In addition, the association between Multiple Sclerosis (MS) and IBD has been suggested, apart from their common epidemiological and immunological patterns, also due to observations of increased incidence of both IBD among MS patients and MS among IBD patients. Accordingly, a bidirectional link between gastrointestinal inflammation and neurodegeneration/ neuroinflammation, in accordance with the idea of the ‘gut–brain axis’, has recently emerged. In particular, enteric dysbiosis, translocation of bacterial products as well as inflammatory cells/soluble factors derived from the inflamed intestinal mucosa across the gut epithelial- and blood-brain-barrier (BBB) have been implicated as major factors for structural and functional alterations in the CNS. While the concept of a pathophysiological gut-brain axis is increasingly recognized, in-depth characterization of inter-organ communication to identify immunological checkpoints that control this network during health and disease, is limited. The overall aim of this clinical research unit is to delineate the interactions between the intestinal and the nervous system across the gut-brain axis in the context of immune-mediated inflammatory and degenerative diseases. Cross-fertilization between the research foci immunology and neuroscience will allow us to gain unique new insights into the pathogenesis of these disorders to establish the necessary scientific foundation for the future development of novel diagnostic and therapeutic tools. Controlling the disease activity in one of the organs may reduce the risk of developing inflammation/degeneration in the other direction of the axis, potentially owing to a reduction in disease activity and modulation of the gut-brain axis. To reach this goal, we will combine our strong expertise in basic and clinical neuroimmunology, neurodegeneration, gastroenterology, and mucosal immunology. Using a strictly interdisciplinary approach, we aim for the replacement of the traditionally organ centered perception of inflammation. In the long-term perspective, we aim to obtain a comprehensive understanding of gut-brain communication for the identification of novel biomarkers, therapeutic targets, interventional strategies and predictors of treatment response to improve patient care.
Contact: Prof. Dr. Beate Winner, Department of Stem Cell Biology
Magnetic resonance imaging (MRI) at ultra-high field (UHF) strengths, such as 7 Tesla, offers unique possibilities for non-invasive tissue characterization. Nevertheless, clinical applications are currently still rare, and present clinical research studies mostly focus on morphological imaging. Advanced tissue contrasts, such as chemical exchange saturation transfer (CEST), X-nuclei MRI and microstructural imaging, have already provided valuable information beyond morphology. The combined application of these MRI contrasts would provide a sound basis for highly insightful multispectral MRI. However, obtaining such an MR-signature scan is currently limited by long acquisition times, poor data quality due to radiofrequency field inhomogeneities, patient motion and the increasing difficulty of interpreting the large amount of complex multispectral data. To fully unleash the potential of 7T MRI, we aim to establish “MR biosignature imaging” augmenting morphological imaging. For this purpose, we will first establish the methodological base by developing complementary fast MR techniques for the unique non-invasive characterization of different tissues, their chemical composition and their microstructure. To turn MR-signatures into pathology-specific MR biosignatures for non-invasive tissue characterization, we will use three clinical research applications. We expect that the MR biosignatures, once established, will reveal early signs of neuro-degeneration, tissue degeneration in chronic diseases and provide insight into cancer risk factors. We are convinced that such an MR biosignature scan would provide a more comprehensive insight into disease processes than the sum of the individual contrasts. To achieve these goals, we will unify the efforts of MRI physicists, engineers, data scientists as well as clinicians. To enable the acquisition of high MR data quality, ‘smart’ hardware will be developed that combines radiofrequency (RF) coil technology with multiple receive and transmit elements as well as integrated multimodal RF coil load- and radar-based motion tracking technology. Data science will be employed to identify the most important data features of the MR-signature scan and to accelerate data acquisition. This research unit (RU) will build on a strong research environment and infrastructure in Erlangen. At the Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), outstanding research groups in the field of data science, machine learning and electrical engineering will contribute by working closely with the researchers of the University Hospital Erlangen (UKER), i.e. with three recently established research groups focusing on novel MR contrasts and UHF MRI, and with collaborating clinical researchers. A dedicated clinical 7T system will be used, offering unique possibilities for combining cutting-edge technological and clinical research.
Contact: Prof. Dr. Armin Nagel, Institute of Radiology