The role of oxalate transporters in maintaining kidney health

Our laboratory focuses on the mechanisms involved in maintaining oxalate homeostasis. Oxalate is a component of various foods and is absorbed via the intestine. High urinary oxalate concentrations lead to kidney stones, the second most common kidney disease after hypertension. Furthermore, we have shown that elevated blood oxalate concentrations are associated with cardiovascular disease. We are working translationally and recently demonstrated that oxalate uptake in the intestine can be reduced via an enzyme isolated from bacteria in patients.

Innate lymphoid cells, IL-22 and liver regeneration

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, contributes to tissue physiology and health. 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 health span.

The role of DNA damage response signaling in chronic kidney disease

Our research group studies the underlying mechanisms of chronic kidney disease (CKD). Acute and chronic kidney injury has been increasingly recognized as a global public health concern, associated with high morbidity, and mortality. Acute kidney injury is frequent, occurring in 21% of hospital admissions and leads to CKD regardless of the cause.

To generate an atlas of cellular senescence in different types and severity grades of liver disease

Cellular senescence occurs in the liver in health and disease. Senescence relates to a status of cell cycle arrest, which becomes more prevalent with increasing age and which develops as the consequence of liver disease.1 Due to subsequent changes in cell morphology and functionality senescent cells may prompt disease progression and the development of disease-related complications. Detection of senescence and deciphering of its underlying mechanisms may help identifying novel targets to develop preventive treatment strategies to halt the development of liver disease related complications such as fibrosis, inflammation, and ultimately cirrhosis. Therefore, this project seeks to address the following aspects:

Healthy skin homeostasis? – Does anti-cytokine treatment restore the physiological and immunological function of the skin?

Our laboratory focuses on the immunological and molecular pathomechanisms of the skin with the aim to identify approaches for personalized and preventive medicine. One group of our translational research interests are chronic inflammatory autoimmune diseases of the skin.

Learning from outliers – Identifying determinants of kidney survival in non-progressive ADPKD

Not Everything Is “Genetic”, but Genes Are Involved in Everything (adapted from Kenneth M. Weiss). 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.

The role of the OSM pathway in maintaining intestinal homeostasis

The mammalian gastrointestinal tract contains the largest number of immune cells and harbors a large and diverse population of commensal bacteria that exist in a symbiotic relationship with the host. The gut-resident immune cells are separated from our microbial residents by a single layer of intestinal epithelial cells (IEC). The dynamic cross-talk between IEC, the intestinal microbiota, and local immune cells represents a cornerstone of intestinal homeostasis. The balance between the various immune cell populations and tonic cytokine signals play an important role in determining thresholds of tolerance and immunity in the intestine.

Does fasting re-program inflammatory immune cells?

Diet is an important factor for a healthy life. For the most part of human history, the next meal was not a given. Hence, there was a strong selection pressure for adaptation to periods of no or low food consumption during our evolution. Consequently, today’s excessive calorie intake, as it is typical for diets in the western world, results in increasing occurrence of systemic inflammation and widespread diseases. In contrast, calorie restriction has been shown to improve numerous chronic diseases and to prolong the healthy lifespan. In my group, we are re-thinking health in the context of evolutionary adaptation to low food energy intake. Specifically, we focus on the identification of cellular and molecular mechanisms how reduced calorie intake maintains health, prevents and improves inflammatory diseases, and prolongs healthy life.

Dissecting tissue-homeostatic functions of group 2 innate lymphoid cells using novel genetic tools

Type 2 Inflammation, innate lymphoid cells, tissue-homeostasis, neuro-immune interactions.

NF-κB in homeostasis, acute inflammation, and mucosal healing

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. Recent studies showed that crosstalk between epithelium and immune cells changes in health and disease, and that is in part due to altered functions of NF-κB. Our group aims to decipher that crosstalk and identify the changes. Our research is highly interdisciplinary and spans different fields including biochemistry, immunology, stem cell biology, and cancer biology.

Deciphering the role of macrophages for allograft quality and survival

Our group is studying immune-mediated mechanisms of solid organ allograft rejection. Worldwide, the number of available donor organs is decreasing. Moreover, due to demographic changes in modern societies the number of individuals with an advanced age >65 years is steadily increasing. This results in a higher number of patients diagnosed with progressive chronic kidney disease (CKD) constituting a potential kidney transplant recipient group. Accordingly, chronological donor age is also a major risk factor for allograft dysfunction, as grafts from older donors are more susceptible to ischemic injury and prone to restricted allograft outcome. Despite modern immunosuppressants, overall long-term survival of solid allografts is limited. The infiltration and activation of immune cells is one of the key mechanisms for chronic allograft failure, but the detailed molecular and cellular mechanisms underlying the complex interplay between donor and recipient – finally resulting in the rejection of the graft – are still not understood. Consequently, a better understanding of both, donor organ quality and allograft rejection is mandatory in order to overcome the current limitations of insufficient numbers of donor organs – and restricted allograft survival in the long term.

The role of the primary cilium in the physiological autoregulation of the pulmonary vasculature

Maintenance or restoration of vascular homeostasis are critical determinants of health throughout life. Of late, the primary cilium has been identified as a key regulator of vascular homeostasis and regeneration. While impairment of primary ciliary structure and signaling can promote vascular disease and vascular remodeling, strategies aiming to preserve or restore ciliary function emerge as novel therapeutic approaches to maintain vascular health.

Role of mechanical signals for growth and regeneration of bones / LR signaling in aging and joint trauma as a potential cause of osteoarthritis

Our laboratory investigates the cellular and molecular causes of osteoarthritis, the most common joint disease in adults worldwide. To date, there is no therapy that alters the course of the disease. The onset of osteoarthritis is closely associated with advanced age and joint trauma, and the signaling pathways involved are still poorly understood. Therefore, we aim to gain a better understanding of the control of cartilage and bone formation and degradation in joints during aging and trauma. We will first study these processes in the healthy state and then compare them with their regulation in osteoarthritis. The focus here is on the cartilage-forming cells, the chondrocytes, as well as the cells of the synovial membrane and the subchondral bone. The changes in cartilage and bone metabolism identified in this way offer potential targets for causal therapies by biological regeneration of articular cartilage.

The role of Muc5b in lung homeostasis and onset and progression of interstitial lung disease

Mucociliary clearance is the primary innate defense mechanism of the lung and crucial to maintain lung homeostasis and health. Mucociliary clearance relies on motile cilia on the surface of epithelial cells and a protective mucus gel layer entrapping particles and pathogens to be cleared from the lungs. Recent evidence suggests that the secreted mucin MUC5B that is crucial for the formation of the mucus gel and proper mucociliary clearance is also implicated in the pathogenesis of interstitial lung disease (ILD). ILD can affect children and adults and is characterized by interstitial inflammation, rapid progression of pulmonary fibrosis and subsequent disruption of the alveolar gas exchange ultimately leading to respiratory failure. The understanding of the pathogenesis remains limited and ILD is usually diagnosed in advanced stages when irreversible lung damage has already occurred. Further, only limited therapeutic options are available, which so far, cannot prevent progression of pulmonary fibrosis. By conditional deletion of Nedd4-2 (Nedd4-2-/-) in lung epithelial cells of mice, we recently generated the first mouse model that develops spontaneous pulmonary fibrosis sharing key features with ILD patients allowing us to study lung homeostasis at baseline and early dysregulation leading to the development of interstitial lung disease.

Neuro-immune interactions in the GI tract: Control of gut homeostasis and function by intestinal regulatory T (Treg) cell-derived endogenous opiods

Chronically stimulated surfaces of the body, in particular the gastrointestinal (GI) tract, are major sites where immune cells traffic and reside. Because mucosal surfaces are constantly challenged by fluctuating environmental perturbations, immune cells at these sites display a remarkable adaptive capacity in order to fend off microbial challenges and safeguard organ homeostasis and health. The Neumann lab is specifically interested in the molecular basis of lymphocyte adaption to mucosal organs. The goal of our research is to understand the genetic, epigenetic and transcriptional mechanisms that determine the tissue-specific functions of distinct lymphocyte populations. Furthermore, we aim to identity the specific (micro)environmental cues that trigger tissue adaptation. In addition, a major focus of our research lies on the crosstalk between gut lymphocytes and distinct intestinal tissue cells, such as epithelial or neuronal populations, to better understand the cellular networks that are in place to establish and maintain intestinal health.

Epigenetic mechanisms in T cell senescence and aging

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). Our laboratory investigates the epigenetic regulatory mechanisms in immune cells, which have to react particularly flexibly to external influences (infection, inflammation, microbiota, aging, 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.