Emmy Noether and othe junior research groups
- Emmy Noether Junior Research Group
- Nuclear synthesis of acyl-CoAs in chromatin reprogramming and gene activity
- Project leader
- Dr. Marta Russo
- Instiution
- Biomedical Center (BMC)
- Funding
- since 2025
- website
- Project description GEPRIS
- Topics
- Metabolism and gene expression, two fundamental biological processes, are closely linked and interact in the regulation of cell functions and physiological activities. Metabolic enzymes and their by-products, 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 cell 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 maintain their functionality and ability to produce their metabolites when bound to mediator in the cell 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 cell 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. However, 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 because 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 elucidate 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 leader
- Dr. Vincent Gaertner
- Institution
- Children's hospital and children's outpatient clinic
at Dr. von Hauner Children's Hospital - Funding
- since 2025
- Website
- Project description GEPRIS
- Topics
- Every year, more than 800,000 children worldwide die as a result of perinatal asphyxia, making it the most common cause of death in children under the age of five. Despite this, 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 babies 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. There are currently 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 (the so-called "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 investigating 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 ageing heart: exploring new markers of ageing and investigating new treatment options
- Project leader
- Dr. Daniel Reichart
- Institution
- Department of Medicine I
- Funding
- since 2023
- Website
- Project description GEPRIS
- Topics
- For decades, the life expectancy worldwide has increased steadily. Currently, every second German citizen is older than 45 and every fifth above 66 – with upward tendency. At the same time, ageing also poses the significant risk for chronic diseases such as cancer, neurodegenerative or cardiovascular diseases, the latter being the most common. At molecular level, the ageing process of the heart is driven by an imbalance of harmful (e.g. DNA or epigenetic changes, cellular senescence) and reparative mechanisms, resulting in a gradual loss of cellular resilience and integrity. This may lead to an increased vulnerability to heart diseases with subsequent cardiac dysfunction. Despite of the same chronological age of two individuals, the ageing of these two can proceed at different speeds due to the heterogeneous expression of molecular ageing processes; thus, two different biological ages will result. With single cell RNA sequencing, the gene expression patterns of individual cells can be measured, which allows the heterogeneity of the cell types of a heart to be characterized with high sensitivity. In order to be able to pick up all heart cell types of different sizes (especially the cardiomyocytes), the cell nucleus will be extracted before single cell measurement (“single nucleus RNA sequencing”, snRNA-seq). With the help of snRNA-seq, first the healthy and later the diseased human heart was mapped at single cell resolution. In diseased hearts with systolic dysfunction, cardiomyocytes were found decreased and a secretory phenotype of fibroblasts was increased, which promotes cardiac fibrosis development and "adverse cardiac remodeling". In addition to the RNA measurement – in single nuclei or directly in tissues – the simultaneous display of chromatin accessibility at single cell level is also possible, which allows additional insights into the epigenetic regulation. By combining these two modalities, the healthy, ageing human heart will be characterized at single-cell level in order to depict ageing-associated changes in i) cellular composition, ii) gene expression and iii) epigenetic patterns. This will help to filter molecular factors that lead to the heterogeneous rates of biological heart ageing; at the same time, common characteristics of the ageing and diseased heart will be determined. For this purpose, heart tissues from healthy donors will be used and sequenced at single cell level. The results will be correlated and validated with ageing wild-type mice. Molecular signals that trigger ageing-associated negative effects such as "adverse cardiac remodeling" will be identified and treated by "small interfering" RNAs (siRNAs) first 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. 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 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