We are a reproductive immunology group studying pregnancy, allergy, the gut microbiome and immune system development. Our research focuses on the “developmental origins of health and disease” hypothesis, which posits that perinatal environmental exposures (during the fetal and early neonatal life stages), can influence immunity and subsequent disease susceptibility later in life. Inappropriate nutritional inputs in early life can result in metabolic malprogramming of vital regulatory pathways which permanently alter the immune system, resulting hyperreactive inflammatory processes that persist for the lifetime of an individual.1 As an example of this, childhood overweight and obesity present a serious public health concern, and are associated with an increased risk for non-communicable diseases such as asthma.2 To address the increasing morbidity and mortality from non-communicable diseases, it is therefore crucial to understand the mechanisms that contribute to this phenomenon. The aim of this proposal is to use a mouse model to understan
We are a reproductive immunology group studying pregnancy, allergy, the gut microbiome and immune system development. Our research focuses on the “developmental origins of health and disease” hypothesis, which posits that perinatal environmental exposures (during the fetal and early neonatal life stages), can influence immunity and subsequent disease susceptibility later in life. Inappropriate nutritional inputs in early life can result in metabolic malprogramming of vital regulatory pathways which permanently alter the immune system, resulting hyperreactive inflammatory processes that persist for the lifetime of an individual.1 As an example of this, childhood overweight and obesity present a serious public health concern, and are associated with an increased risk for non-communicable diseases such as asthma.2 To address the increasing morbidity and mortality from non-communicable diseases, it is therefore crucial to understand the mechanisms that contribute to this phenomenon. The aim of this proposal is to use a mouse model to understan
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 likely to reveal unsuspected pathways by which the immune system might be plumbed to improve health and healthspan. These lines of research have suggested new functions of the immune system for processes such as tissue homeostasis, morphogenesis, metabolism, regeneration and growth. Our research is developing by crossing boundaries of disciplines (immunology, microbiology, developmental biology, stem cell biology, nutrition sciences, tumor biology, regenerative medicine etc.) and is, by nature, highly interdisciplinary.
Our laboratory focuses on the immunological and molecular pathomechanisms of the skin with the aim to identify approaches for personalized and also preventive medicine. One of our translational research interests are chronic inflammatory autoimmune diseases of the skin. In addition to preclinical models and in vitro methods, we use skin and blood samples from patients for biomarker identification. We are particularly interested in specialized T cell responses, cytokine signaling pathways and the application of liquid biopsy in chronic inflammatory skin diseases.
Our group is interested in immune and kidney epithelial cell interactions. Using analysis of cells in the urine, kidney biopsies and cell culture we focus on analyzing human patient samples to answer the overarching question, how the kidneys are damaged and how they recover from injury.
Health and disease is not well defined for tuberculosis, one of the most important infectious diseases. Here, we propose to build upon an existing cohort study of tuberculosis contacts in Berlin to define a recently recognized new form of TB, subclinical TB, using a novel phage-based assay. People with evidence of subclinical TB will be high priority contacts for prophylactic anti-TB treatment to prevent progression to active TB.
Our group is interested in the identification and investigation of genetic, clinical, and environmental factors determining the 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.
Neuro-immune interactions.
The kidney has a central role in absorbing nutrients for tissue function and health. Vice versa, cellular toxins have to be excreted by the kidney into the urine to avoid systemic accumulation and toxicity. Our working group recently described a patient who has a genetic defect of the sulfate transporter SLC26A1. SLC26A1 has been postulated to mediate sulfate absorption in exchange for oxalate. Sulfate is an important nutrient for musculoskeletal as well as cardiovascular health. Our patient described with a mutation of SLC26A1 has been suffering from a musculoskeletal disorder. Additional studies performed in large population cohorts (UK Biobank) have now shown that defective sulfate transport may be more common than expected and is related to bone fractures (manuscript in revision). We hypothesize that the anion exchanger SLC26A1 mediates sulfate (nutrient) absorption in the kidney for exchange of oxalate (toxin). In order to investigate this as part of a doctoral thesis, we have generated human pluripotent stem cells deficient for SLC26A1. The doctoral student will be culturing these stem cells to so called kidney organoids following a protocol established in our laboratory (Constantin Dickel, Re-Thinking Health Class, 2022). The doctoral student will be performing transport studies using radioactive tracers and examine the effect of sulfate and oxalate transport defects on cellular toxicity (metabolomics, mitochondrial function).
Our group “Signal Transduction in Health and Disease” (Department of Hepatology and Gastroenterology, Charité Campus Mitte and Campus 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. Our current projects range from determining the role of the transcription factor in epithelial regeneration in colitis and in inflammatory bowel diseases (Re-Thinking Health, 2022), to refining analgesia (3R funded project), to investigating the role of NF-κB in cellular senescence in the gut (DFG) or its role in metabolism.
Role of tissue resident macrophages during the maintenance of tissue homeostasis and the prevention of inflammatory disorders.
Pulmonary arterial hypertension is a cardiopulmonary disease that is characterized by profound remodeling of the pulmonary vascular tree and has a poor prognosis if left untreated. Current therapeutic approaches rely on vasodilatory drugs and do not address the underlying cause of vascular remodeling. Investigating the pathophysiology of pulmonary arterial hypertension on a novel, in vitro microvasculature-on-chip model allows to track changes of the vascular system and the dynamics of individual cell types specifically in a temporal and spatial context that was not possible before. As such, microvasculature-on-chip models – in combination with advanced imaging modalities, state-of-the-art transcriptomic and proteomic analyses, and functional read-outs – open up unprecedented avenues for the discovery of new disease mechanisms and therapeutic targets.
Alarmins can be used as markers for pathologies even prior to obvious onset of disease. Moreover, interference with alarmins and their signaling pathways provides a powerful tool for the manipulation of several types of diseases (Liew et al., Nat Rev Immunol. 2016; Peine et al., Trends Immunol. 2016).
The microbiota, i.e. the entirety of microbes in an organism, plays a crucial role in the maintenance of health and the development of diseases. A diverse microbiota not only produces essential metabolites and supports the uptake of nutrients, but also is important for the development of a functional immune system.1,2 Mice that are born and kept under laboratory, specific pathogen free (SPF) conditions have only a reduced microbiome and thus, possess an immature immune system, resembling more likely a newborn than an adult human.3 This may have contributed to failure in translating results from previous preclinical studies into the clinics. However, mice are an invaluable tool in preclinical research, as their genome is well studied and various genetic models exist that are necessary to understand molecular mechanisms of disease pathogenesis. To improve translatability, Wildling mice have been developed that harbor a natural microbiome, comparable to mice in the wild, and consequently, have an immune system being more similar to that of an adult human.4 As part of the “Wildling Mice in Health and Disease (HeaD)”-Consortium at Charité we will validate the Wildling model in our preclinical mouse model of muco-obstructive lung disease, called βENaC-transgenic (βENaC-Tg) mice.5 These mice overexpress the β-subunit of the epithelial Na+ channel (ENaC) specifically in the airways to produce airway surface dehydration, resulting in the development of airway mucus plugging, dysbiosis, chronic inflammation and structural lung damage, i.e. key features of patients with cystic fibrosis (CF) and other muco-obstructive lung diseases.5-7 Although this mouse model mimics airway surface dehydration as a key disease mechanism in CF lung disease, important clinical aspects like spontaneous Pseudomonas aeruginosa infections are not recapitulated in SPF mice. Hence, we hypothesize that a natural airway microbiome will critically affect the infection status in βENaC-Tg mice including the development of chronic Pseudomonas infection that is a key determinant of lung disease severity and lung function decline. Such a novel model of chronic Pseudomonas infection would enable in vivo testing of novel therapeutic strategies to eradicate Pseudomonas from the airways and thus, target a high unmet need in patients with CF.
Chronically stimulated surfaces of the body, in particular the gastrointestinal (GI) tract, are major sites where immune cells traffic and reside. Since the intestinal surface is constantly challenged by fluctuating environmental perturbations (microbiota, diet, pathogens), immune cells at this site display a remarkable capacity to adapt their functionality in order to safeguard organ homeostasis and health.
The Neumann lab is specifically interested in the molecular basis of immune cell adaption to the GI tract. The goal of our research is to understand the molecular mechanisms that determine the gut-specific functions of distinct immune cell populations. Furthermore, we aim to identify the specific (micro)environmental cues that trigger adaptation of immune cells in the gut. In addition, a major focus of our research lies on the crosstalk between gut immune cells and distinct intestinal tissue cells, such as epithelial or neuronal cell populations, to better understand the cellular networks that are in place to establish and maintain intestinal health.
Disease prevention is taking a central role in tackling the burden of cardiovascular disease in our aging society. Thrombotic cardiovascular diseases such as venous thromboembolism, stroke and myocardial infarction are main drivers of morbidity and mortality worldwide. A central pathomechanism in these thrombotic cardiovascular diseases is termed thromboinflammation and arises from a deleterious dysregulation of an evolutionary conserved host defense mechanism involving platelets, the innate immune and coagulation system. There is an unmet clinical need for a better mechanistic understanding of thromboinflammation, in order to novel regulatory mechanisms that may pave the way for potential therapeutics, biomarkers and preventive measures. By pursuing this aim we established an across-species approach to investigate the paradox that long-term immobility during hibernation in brown bears and patients with spinal cord injury (SCI) does not increase the risk of thrombosis.