Emmy Noether Junior Research Groups

Emmy Noether Junior Research Group: Nuclear synthesis of acyl-CoAs in the reprogramming of chromatin and gene activity
project manager: Dr. Marta Russo
furnishings: Biomedical Center (BMC)
promotion: since 2025

website: Project description GEPRIS
Topics: Metabolism and gene expression, two fundamental biological processes, are closely linked and work together to regulate cell functions and physiological activities. Metabolic enzymes and their byproducts, metabolites, play a crucial role in altering chromatin structure and thereby influence gene expression. Traditionally, scientists have focused primarily on studying metabolic pathways in cellular compartments outside the nucleus, particularly in mitochondria. However, there is growing evidence for the activity of metabolic enzymes within the cell nucleus, particularly enzymes involved in acyl-coenzyme A metabolism, which directly affects histone modifications. I recently discovered the existence of three metabolic enzyme complexes in the nuclei of mammalian cells, in addition to their known localization in mitochondria. Significantly, these enzyme complexes interact with the mediator complex, an important mediator of gene transcription by RNA polymerase II. I was able to show that these nuclear enzymes retain their functionality and ability to produce their metabolites when bound to Mediator in the nucleus, while also accumulating at Mediator target genes. Consequently, their products contribute to histone modification and gene expression regulation. This discovery allows us to propose a fascinating hypothesis: Metabolic enzymes in the nucleus regulate gene expression through the production of metabolites. We believe that this mechanism could be particularly important for cells such as macrophages, i.e., immune cells that rapidly adapt their gene activity when they detect danger signals. Nevertheless, essential molecular details of the interaction between nuclear metabolic enzymes and the transcription machinery remain unclear. My goals are therefore: 1) to investigate the influence of these nuclear enzymes on gene regulation; 2) to identify new protein interactions of these enzymes in the cell nucleus; and 3) to analyze the structure of these enzymes and their interactions with the mediator complex. Using advanced 'omics-based approaches, metabolite tracing, and imaging techniques, my research aims to elucidate the functional dynamics and structural features of these interactions. Macrophages will serve as an important cellular model, as they rapidly reprogram their gene expression and metabolism in response to danger signals. In summary, the research aims to provide insights into the crucial interplay between metabolism and transcriptional regulation and to explore the role of nuclear metabolic enzymes in gene regulation.

Source: GEPRIS

Emmy Noether Junior Research Group: From EAGLE to LEOPARD – A comprehensive approach to better understanding the neonatal transition phase and improving respiratory support for newborns and premature babies in the delivery room
project manager: Dr. Vincent Gaertner
furnishings: Children's hospital and children's polyclinic
at Dr. von Hauner's Children's Hospital
promotion: since 2025

website: Project description GEPRIS
Topics: More than 800,000 children worldwide die each year as a result of perinatal asphyxia, making it the leading cause of death in children under the age of 5. Nevertheless, the transition from fluid-filled to air-filled lungs after birth is still not adequately understood. Between 5-10% of live births are premature, and almost all premature infants require respiratory support through the application of positive end-expiratory pressure immediately after birth. This helps to maintain functional residual capacity (FRC) and prevent hypoxia. To date, there have been no relevant clinical studies on the effect of different pressure levels immediately after birth, and recommendations are based solely on expert opinion. Accordingly, PEEP levels vary greatly between centers (between 5-20 cmH2O). Inadequate lung ventilation during postnatal stabilization (known as the "golden hour") leads to the need for mechanical ventilation and is associated with mortality and long-term illness. The correct initial pressure level in this phase is therefore crucial, but still unknown. Electrical impedance tomography (EIT) allows real-time visualization of intrapulmonary volume changes with high temporal resolution and is an ideal non-invasive method for measuring lung volumes in premature and newborn infants. Inflammation of the lungs is a crucial component in the cascade of lung damage, and understanding the (sub-)cellular mechanisms in this cascade could help improve future clinical management. In this proposal, we describe a six-year research program with the following objectives: (1) to better understand the physiology of neonatal transition, (2) to directly improve the clinical management of very preterm infants by conducting a large randomized clinical trial to investigate the effect of different pressure levels on patient-relevant outcomes, and (3) to combine knowledge about these interventions with preclinical (electro)physiological and inflammatory data to define pathophysiological pathways. Specifically, we will conduct the following studies: 1. Assessment of lung physiology during the first breaths of life in term infants; 2. Development of a patient-centered ordinal outcome for neonatal studies; 3. Effect of high vs. low PEEP immediately after birth on respiratory outcomes in very preterm infants – LEOPARD study; 4. Mechanisms of lung ventilation during physiologically based umbilical cord management; 5. Effect of different PEEP on the lung physiology of preterm infants; 6. Effect of different PEEP on proteome profiles and inflammatory markers in preterm infants; 7. Establishment of the research center after the current funding period.

Source: GEPRIS

Emmy Noether Junior Research Group: The aging heart: Identification of new biomarkers of aging and evaluation of new treatment approaches
project manager: Dr. Daniel Reichart
furnishings: Medical Clinic and Polyclinic I
promotion: since 2023

website: Project description GEPRIS
Topics: Life expectancy has been steadily increasing worldwide for decades. In Germany, one in two people is currently over 45 years old, and one in five is over 66—and the trend is rising. At the same time, age also poses a significant risk for chronic conditions such as cancer, as well as neurodegenerative or cardiovascular diseases, with the latter being the most common. The aging process of the heart is caused at the molecular level by an imbalance between harmful (e.g., DNA or epigenetic changes, cellular senescence) and repair mechanisms, resulting in a gradual loss of cellular resilience and integrity. This ultimately leads to increased vulnerability to heart disease with subsequent cardiac dysfunction. Despite two individuals being the same chronological age, the heterogeneous expression of these molecular processes can cause them to age at different rates, resulting in two different biological ages. Single-cell RNA sequencing measures the gene expression pattern of individual cells, which allows the heterogeneity of heart cell types to be characterized with high sensitivity. In order to be able to sample all heart cell types of different sizes (especially cardiomyocytes), the cell nuclei ("single nucleus RNA sequencing," snRNA-seq) must be extracted before the single-cell measurements. With the help of snRNA-seq, the healthy human heart was first mapped, followed by the diseased heart. In diseased hearts with systolic dysfunction, for example, a reduced number of cardiomyocytes and a secretory phenotype of fibroblasts were observed, which promotes fibrosis in the heart and thus causes adverse cardiac remodeling. In addition to RNA measurement—in individual cell nuclei or directly in tissues—it is also possible to simultaneously visualize chromatin opening at the single-cell level, which provides additional insights into epigenetic regulation. By combining the two methods, the aim is now to characterize the healthy, aging human heart at the single-cell level in order to visualize age-associated changes in i) cellular composition, ii) gene expression patterns, and iii) epigenetic patterns. The aim is to identify molecular factors that ultimately determine the heterogeneous rate of biological heart aging; at the same time, common characteristics of the aging and diseased heart will also be investigated. For this purpose, heart tissue from healthy donors will be used and sequenced at the single-cell level. The results will be correlated and validated with aging wild-type mice. Molecular signals that trigger age-associated negative effects, such as adverse cardiac remodeling, will be identified and treated with small interfering RNAs (siRNAs), initially in vitro and later in vivo.

Source: GEPRIS

Emmy Noether junior research group: Multi-omic characterization of the immune mechanisms driving human atheroprogression
Project leader: Dr. Marios Georgakis
Institution: Institute for Stroke and Dementia Research (ISD)
Funding: since 2023

Website: Project description GEPRIS
Topics: Atherosclerotic cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. The medical management of atherosclerosis has dramatically improved in recent decades with the development of effective cholesterol-lowering strategies and the aggressive management of other vascular risk factors. However, the residual rates of CVD continue being unacceptably high thus calling for new treatment paradigms in lowering risk. An extensive line of research supports that an immune response within the arterial wall drives atheroprogression and recent trials provided proof-of-concept that immunotherapeutic agents can lower CVD risk. However, the clinical translation of atheroprotective immunotherapies is lagging behind due to the lack of drugs that precisely modulate the immune response underlying atheroprogression and the lack of specific biomarkers of atheroinflammation that could be used to personalize treatments. This proposal is focused on addressing these two key challenges. The overarching goals are to detect novel drug targets for immunotherapies and uncover endophenotypes of atheroinflammation. Extending and scaling a pipeline established by my previous work, I will first aim to dissect immune pathways underlying CVD by leveraging large-scale proteomic, single-cell transcriptomic, and metabolomic data and anchoring them to genetic information. Integrating omics data from human atherosclerotic samples I will explore proteomic, transcriptomic, and cellular endophenotypic signatures of atheroinflammation that mediate the effects of modulating promising drug targets on risk of CVD. Utilizing cutting-edge single-cell and spatial transcriptomic technologies, I will then explore the molecular immune signatures of human carotid atherosclerotic plaques that reflect atheroprogression. Finally, by integrating these high-resolution molecular data with carotid MRI and peripheral blood proteomic analyses in a machine learning framework, I will aim to detect accessible in vivo biomarkers of the immune landscape of atherosclerosis. The findings from the proposed research will open the road for the clinical translation of more precise and personalized immunotherapeutic strategies with the ultimate goal of lowering the global burden of CVD.

Source: GEPRIS

Emmy Noether junior research group: Deciphering the genetic basis of human immune response variation
Project leader: Dr. Sarah Kim-Hellmuth
Institution: Department of Pediatrics, Dr. von Hauner Children’s Hospital
Funding: since 2022

Website: Project description GEPRIS
Topics: The human immune system plays a key role in host protection against microbial infections, autoimmune and inflammatory diseases, cancer, metabolism, and ageing. Large genome-wide association studies have implicated hundreds of genetic loci in immune-related genes highlighting the immune system’s role in the biological mechanism underlying genetic risk to numerous diseases. However, for the vast majority of these genetic variants, we have little understanding of their functional effects and their context-specificity. This challenge is addressed by the proposed research. The overarching aim is to characterize the genetic basis of human immune response variation, which will advance our understanding of disease-associated variants and answer questions of genome function plasticity that is shaped by gene-by-environment interactions. For this purpose, we will first study the in vivo transcriptional immune response using long-read cDNA-sequencing in a cohort of 250 extensively characterized participants of a yellow fever vaccination study. Integrating the transcriptional data then with the rich genetic and molecular characterization available for this cohort provides a unique opportunity to build a multi-layer map of the genetic basis of immune response variation. This approach will develop a roadmap for complex traits at large and enable the move from genetic discovery to functional interpretation and ultimately clinical impact.

Source: GEPRIS

Emmy Noether junior research group: Understanding the regulatory mechanisms governing combinatorial chromatin states
Project leader: Dr. Guillermo Rodrigo Villaseñor Molina
Institution: Chair of Molecular Biology, Biomedical Center (BMC)
Funding: since 2021

Website: Project description GEPRIS
Topics: At the time of writing, 22 types of histone modifications have been described, including acetylation, citrullination, methylation, phosphorylation, and ubiquitination. With eight modifiable amino acid residues at about 138 positions on five canonical histone variants, more than 550 possible histone modifications have been reported. Several of these chemical marks can coexist on the same nucleosome resulting in an immense theoretical number of combinatorial possibilities. Bivalent chromatin and its associated histone modifications, H3K4me3 and H3K27me3, is perhaps the best-described example of a combinatorial chromatin state known to date. Despite years of intense research on bivalent chromatin, many fundamental questions remain unanswered. How is bivalent chromatin established and maintained in pluripotent cells? How are bivalent sites kept accessible and hence transcriptionally responsive? Are the same factors associated with bivalent chromatin in different cell types? In the first two aims of this proposal, my group will combine experimental and computational approaches to answer these fundamental questions in a quantitative and comprehensive manner. On the experimental side, my group will combine genome-wide assays with rapid protein depletion strategies to carry out mechanistic studies at unprecedented temporal control under defined conditions in mouse embryonic stem cells. In the final part of this project, we will venture into new territory. To date, only a few examples of new combinatorial chromatin states are known. However, these results open the exciting possibility for the existence of more combinatorial options in mammalian cells. In Aim3 of this project, my team will employ a robust and quantitative chromatin-proteomics approach to explore large combinatorial possibilities at single-nucleosome resolution in three distinct cell types and functionally characterize novel examples. In the future, my team will expand our chromatin-proteomics approach to other cell types and cancer cells to elucidate more combinatorial chromatin modifications.

Source: GEPRIS

Emmy Noether junior research group: Circadian clocks as modulators of metabolic cormorbidity in major depressive disorder
Project leader: Dr. Gregor-Alexander Pilz
Institution: Chair of Cell Biology, Biomedical Center (BMC)
Funding: since 2021

Website: Project description GEPRIS (ger)
Topics: In the dentate gyrus of the hippocampus, neural stem cells form neurons, known as granule cells, throughout life. In the course of this adult neurogenesis, the newly formed cells migrate, mature and integrate into the existing network of the hippocampus. These newly formed neurons play a functional role in specific forms of learning. In addition, altered rates of adult neurogenesis are associated with diseases of the neuropsychiatric spectrum. In order to obtain a complete picture of dynamic adult neurogenesis – from stem cell division to integration – it was necessary to establish a technique for continuous observation of the stem cell and its daughter cells. Continuous two-photon microscopy through a window above the hippocampus enables a precise description of the behaviour of neural stem cells and also the recording of neural activity of granule cells in awake animals. Nevertheless, important questions remain, such as how adult-formed neurons successfully mature and integrate, or what exact influence they exert on the function of the neural network in the hippocampus. Therefore, I would like to address three crucial questions of adult neurogenesis and the function of the hippocampus. Using chronic microscopy, I will investigate the morphological and functional requirements that are crucial for the successful integration of young neurons. In addition, I will investigate molecules and physiological conditions that can positively influence integration. During their maturation and integration, adult-born neurons possess specific physiological properties and fulfil special functions within the network. The exact role that adult-born neurons play in information processing and memory formation in the hippocampus (DG – CA3) over the course of their integration remains unclear. I will investigate this by optically recording neural network activity while simultaneously manipulating the activity of adult-formed neurons in behavioural experiments. For this purpose, a behavioural experiment that specifically addresses the function of the dentate gyrus will be used. Difficulties in retrieving old memories and forming new ones often occur in old age. At the same time, the rate of adult neurogenesis also decreases. The functional role of newly formed neurons, which decline with age, in the function of the hippocampus will also be elucidated using in vivo microscopy. In addition, we want to investigate whether stimulation of adult neurogenesis through various physiological interventions can support or restore functionality and memory formation in the ageing brain. By answering these questions, we can obtain a more complete picture of the role of adult neurogenesis in the function of the hippocampus.

Source: GEPRIS

Emmy Noether junior research group: Cooperation of autoreactive B cells and Th17 cells in the development and progression of CNS autoimmunity
Project leader: Dr. Anneli Peters
Institution: Institute of Clinical Neuroimmunology,
Biomedical Center (BMC)
Funding: since 2017

Website: Project description GEPRIS
Topics: The goal of the proposed project is to investigate the nature of T:B cell collaboration in CNS autoimmunity taking into account the different B cell effector functions that may play a role in the pathogenesis of multiple sclerosis (MS). These include production of autoreactive antibodies, presentation of autoantigen to T cells and production of proinflammatory cytokines both in the periphery and in the CNS. To model those different B cell effector functions, we are employing and have developed different experimental autoimmune encephalomyelitis (EAE) models, each suited to answer specific questions that are still unresolved in the field: (1) Where and how do CNS-reactive B cells evolve during disease development and are disease-associated repertoire changes pathogenic? This question can be addressed in the spontaneous EAE model, the RR mouse, in which myelin-specific B cells are recruited from the endogenous repertoire and required for disease development. We could identify disease-associated changes in the repertoire in this model and can now determine the relevance of these changes for disease manifestation. (2) What functions do B and T cells fulfill in meningeal ectopic lymphoid follicles? We have established the Th17 transfer EAE model featuring large and numerous meningeal eLFs and characterized eLF B cells to be highly activated, poised for germinal center reactions, and engaged in long-lasting contacts with T cells resulting in reactivation of proinflammatory T cells in eLFs. Using our transcriptomic dataset, we are now in the unique position to determine whether similar B cell subpopulations exist in MS patients and thus gain insight into eLF function in MS. (3) What are the cellular sources of the pathogenic cytokine IL-23 and does it also have intrinsic effects on T and B cell pathogenicity? In our novel B cell-driven transfer EAE model, we found that IL-23p19 expression enhances B cell pathogenicity without affecting the T cell or myeloid response and in addition, IL-23p19 deficient T cells failed to transfer EAE. Thus, IL-23p19 may intrinsically affect T and B cell pathogenicity, in addition to the known function of APC-produced IL-23 of promoting terminal differentiation of pathogenic Th17 cells. We have generated IL-23p19fl/fl mice and can now analyze the mechanism of action of IL-23p19 in relation to cellular source in depth.

Source: GEPRIS

Emmy Noether junior research group: Circadian clocks as modulators of metabolic cormorbidity in major depressive disorder
Project leader: Dr. Dominic Landgraf
Institution: Department of Psychiatry and Psychotherapy
Funding: since 2017

Website: Project description GEPRIS
Topics: The scientific work of my research group is focused on the question to what extent a disturbance of circadian rhythms contributes to the comorbid development of various mental and metabolic disorders. Here, the focus is on identifying physiological and molecular targets and – based on these – the development of novel treatments for metabolic and mental disorders. The research work of our laboratory is thus highly translational and includes molecular biology, metabolism, and behavioral experiments in various animal models, and the development and clinical testing of novel treatments.Our results to date, obtained under the current Emmy-Noether grant, strongly demonstrate that circadian disturbances are causally involved in the development of comorbidities of psychiatric and metabolic disorders in both mice and humans. Importantly, we also show that restoration or stabilization of circadian rhythms in mice and humans can simultaneously prevent or significantly improve comorbid conditions. For example, our studies show that cryptochrome-deficient mice lacking endogenous circadian clocks have diabetes-like and anxiety-like phenotypes and that restoration of their endogenous rhythms by viral expression of rhythmic cryptochromes in the suprachiasmatic nucleus reverses these phenotypes. Likewise, stabilization of circadian rhythms by adherence to strict daily schedules in humans improves body weight and concomitant depressive symptomatology and sleep quality. Furthermore, our results from another human study show that stabilizing circadian rhythms in patients suffering from Alcohol Use Disorder who are in withdrawal at our clinic significantly prevents relapse and improves depressive symptoms and sleep quality.Our other studies, which are currently ongoing and for which personnel and additional investment and consumption funds are requested in the present application, aim to identify physiological and molecular interfaces between circadian clocks and the regulation of mental functions and metabolism. On the one hand, this will be done using mice whose circadian rhythmicity is specifically disrupted in the orexin system. On the other hand, we use cutting-edge telemetric EEG equipment to measure the influence of circadian rhythms of neuronal activity and time-of-day-dependent communication of mood-regulating brain regions and a novel screening method to identify signal transduction pathways in these brain regions that are under the influence of circadian control (cisProfiler). These projects will make it possible to develop new and specific targets for personalized therapies that go beyond current, rather non-specific chronotherapies.

Source: GEPRIS

Emmy Noether Junior Research Groups

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