Deadline extended: July 2, 2023 – Are you passionate about scientific questions related to understanding the basis of health and disease? Are you interested in applying your findings to answer clinically relevant questions for molecular prevention and the development of novel therapies?
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In our project, we focus on maladaptive immune responses to prevent multi-morbidity in patients with chronic kidney disease (CKD). Based on our longstanding interest in microbiome-immune interactions in cardiovascular and renal diseases, the planned project involves first proof-of-concept clinical studies side by side with experimental in vitro assays. Our translational project addresses a molecular mechanism that is crucial to maintain health and opens up areas for preventative strategies in line with the Re-thinking health program.
Our research aims to understand the role of tissue-resident cells of the innate immune system in the prevention of chronic inflammatory diseases such as systemic lupus erythematosus. Our goal is to identify mechanisms that maintain homeostasis and prevent chronic inflammation and to determine the role of tissue-resident cells of the innate immune system in this process. Understanding such mechanisms may allow to answer the question of why some patients are susceptible to chronic autoimmune-related inflammatory diseases and others are not, and how to improve/achieve resistance to chronic inflammatory diseases.
The gastrointestinal epithelium is organized into clonal crypts that represent sophisticated anatomical and functional tissue units. The epithelium is intimately associated with the mesenchymal stroma network, and various mesenchymal cell types are essential constituents of the stem cell niche that regulates epithelial homeostasis. The gastrointestinal stem cells give rise to differentiated cells. This process is important to maintain the nutritive absorptive functions of the epithelium as well as to build a barrier against pathogens and toxins from the environment. Recently, it has become increasingly evident that interactions between the epithelium and stroma are vital in regulating the barrier function, allowing tissue adaptations to environmental perturbations1,2. Our research aims at understanding the interplay between the epithelium, stroma and the microbiota. We would like to understand how tissues respond to microbiota alterations or exposure to pathogenic bacteria as well as their toxins. To address this, we are also developing new organoid and assembloid models to recapitulate the cellular networks observed in vivo.
Lymphocytes are composed of both adaptive and innate cells, which differentiate from hematopoietic precursors. These precursors derive from the fetal liver during embryogenesis and from the bone marrow after birth. However, mounting evidence from our previous studies in mice and humans suggests that different tissues, particularly the intestine, can serve as active sites of lymphopoiesis. This proje
Our laboratory investigates the epigenetic regulatory mechanisms in immune cells, which have to react particularly flexibly to external influences (differentiation cues, infection, inflammation, microbiota, etc.). We profile genome-wide epigenetic structures to identify key elements that make a decisive contribution to the generation and function of immune cells during health and in situations of misguided immune reactions (e.g. chronic inflammation and autoimmunity). These elements will help to clarify the molecular reasons for misregulated immune reactions and might represent promising therapeutic targets. Furthermore, in situation where immune cells serve as therapeutic agents to regain health (advanced therapy medicinal products, ATMPs, such as adoptive cell therapy) epigenetic structures may be used as biomarkers for quality and safety control purposes, and also as molecular switches for gene expression (‘epigenetic editing’), which may equip cell products with desired characteristics.
The three-dimensional structure of the genome – the epigenome – contributes significantly to the regulation of gene expression and forms the molecular basis for each cell type-specific transcription profile. In contrast to the DNA sequence, however, the epigenome can be modified by external influences and can therefore adapt the gene expression profile of a cell to new circumstances (e.g. in the case of differentiation, aging, environmental influences, infections, inflammation, etc).
Our laboratory investigates the epigenetic regulatory mechanisms in immune cells, which have to react particularly flexibly to external influences (differentiation cues, infection, inflammation, microbiota, etc.). We profile genome-wide epigenetic structures to identify key elements that make a decisive contribution to the generation and function of immune cells during health and in situations of misguided immune reactions (e.g. chronic inflammation and autoimmunity). These elements will help to clarify the molecular reasons for misregulated immune reactions and might represent promising therapeutic targets. Furthermore, in situation where immune cells serve as therapeutic agents to regain health (advanced therapy medicinal products, ATMPs, such as adoptive cell therapy) epigenetic structures may be used as biomarkers for quality and safety control purposes, and also as molecular switches for gene expression (‘epigenetic editing’), which may equip cell products with desired characteristics.
Diabetics have a higher risk of various infectious diseases including pneumonia. Current estimates suggest that 450 million people worldwide have diabetes, and this number will increase to approximately 700 million by 2045. The increase in diabetes prevalence is thus likely to cause an increase in pneumonia-related morbidity and mortality. A better understanding of the mechanisms underlying diabetes-related dysregulation of the antibacterial immune response may allow to develop more targeted prophylactic strategies to prevent pneumonia in diabetic individuals.
The airway mucosa represents the first line of defense of the respiratory system against pathogens, pollutants, and irritants that are constantly inhaled during tidal breathing. Elimination of these potentially harmful stimuli by mucociliary clearance is an important innate defense mechanism of the lung, which operates through the coordinated function of (i) the motile cilia, (ii) the airway surface liquid layer, and (iii) the mucus layer.
Acute respiratory distress syndrome (ARDS) is a serious complication of infectious or sterile lung inflammation, typically as a consequence of pneumonia or sepsis, with high morbidity and mortality (30%-40%) and presently no pharmacological or mechanistic treatment strategies. This critical knowledge and treatment gap became strikingly evident in the recent COVID-19 pandemic, with ARDS as the main cause of death1,2. ARDS is characterized by a breakdown of the lung vascular barrier and the leak of fluid from the blood into the airspaces, preventing normal lung mechanics and gas exchange. Traditionally, mechanisms of ARDS are studied in animal models, which have, however, translated poorly into the clinical scenario. Here, we will assess mechanisms of lung vascular barrier integrity and regeneration in a novel microphysiological Microvasculature-on-Chip (MOC) model that allows to track vascular morphology and leak as well as the dynamics of individual cell types and their interaction in an unprecedented temporal and spatial context. Here, we will employ this model for the first time to study lung vascular barrier integrity, and to devise strategies for its maintenance in experimental settings mimicking ARDS.
Our group “Signal Transduction in Health and Disease”, Department of Gastroenterology and Hepatology, Charité Virchow, aims to understand the molecular mechanisms involved in tissue homeostasis, inflammation, and resolution of inflammation. Our main focus is on the transcription factor NF-κB and its role in the intestinal epithelium.
Sulfate is an ion that is indispensable for human health. It is necessary for the formation of connective tissues, including bone and cartilage. The kidney plays a central role in body ion homeostasis by reabsorbing electrolytes from the tubular fluid. Specifically, the proximal tubule is a major site for fluid, protein, and nutrient retrieval. Our working groups recently described a patient who presented with unexplained chronic chest pain and a kidney stone.
Tissue homeostatic functions of innate lymphoid cells; Neuro-immune interactions…
Antigen presentation by non-classical antigen-presenting cells has recently been shown to be relevant for priming CD4+ T cell responses. Intestinal innate lymphoid cells (ILCs) and epithelial cells (IECs) have been shown to express class II major histocompatibility complex (MHCII) molecules and prime CD4+ T cell responses toward pathobionts or pathogenic bacteria. More specifically, RORγt ILCs primed microbiota-induced iTreg cell differentiation, whereas it remains unclear how epithelial MHCII expression influences T cell differentiation. MHCII expression by IECs was shown to be relevant for promoting epithelial cell remodelling and supporting intestinal stem cell renewal.1
Our scientific interest lies in understanding how cells of the immune system interact with their surrounding tissues. While molecular and biochemical processes underlying immune cell interactions have long been the subject of research, comparatively little attention has been paid to other stimuli to which immune cells are exposed. Those include physical cues, for example mechanical stimulation. Besides blood and lymph, which serve as liquid transport media and generate shear stress, immune cells in healthy individuals are found to reside in many diverse tissues, which strongly differ in their physical properties. Those properties, impacting on force transmission, are determined by both, the types and behavior of cells that make up the tissues, as well as the structure of the extracellular matrix. Other factors, such as hydrostatic pressure or external forces, also impact mechanically on the tissue under physiological conditions. Examples include the pressure exerted on lungs by respiratory movements, or on the intestine during peristalsis. Thus, immune cells are constantly exposed to mechanical stimuli. How tissue-resident immune cells such as macrophages or innate lymphoid cells sense mechanical stimuli present in the tissues they reside in, how they integrate and react to them, and whether they can adapt to varying mechanical situations in different tissues is not known. Furthermore, inflammatory conditions can alter the physical conditions of tissues. For example, fibrosis profoundly increases the rigidity of tissues. We previously found that the localization of immune cells in fibrotic areas of the lung, was associated with an increased expression of mechanosensors (1). We have also previously shown that innate lymphoid cells localize to fibrovascular niches in the tissue, locations which are sensitive to pressure changes such as edema or fibrosis, due to their proximity to vessels (2).
We hypothesize that in a healthy organism, physical properties of the various organs contribute to immune homeostasis by transducing tissue-specific mechanical signals to immune cells, and tissue-resident immune cells can sense and adapt to the specific mechanical conditions surrounding them. Conversely, changes in these properties in the course of pathologies may affect immune cell activation via distorted force transmission.
Our group is interested in identification and investigation of genetic, clinical, and environmental factors determining onset of chronic kidney disease (CKD) and kidney survival. We make use of next-generation sequencing techniques and deep-phenotyping to identify genetic variants that are predictive for disease progression or convey protection from organ failure. We functionally evaluate identified germline variants in vitro in order to understand underlying molecular mechanisms leading to CKD on the one hand or protecting from kidney failure on the other. By doing so, we aim at defining and targeting molecular switches responsible for health maintenance and disease alleviation.
We study development and function of the innate immune system, in particular of innate lymphoid cells (ILC). A current focus is to obtain a molecular understanding of how the innate immune system, by integrating environmental signals (such as those derived from nutrients, microbiota, circadian rhythm) contributes to tissue physiology. Recent studies have revealed ever more intriguing relationships between innate immune system components and basic developmental and biologic processes that are