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.
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
We are a reproductive immunology group studying pregnancy, allergy and immune system development. The Developmental Origins of Health and Disease hypothesis posits that perinatal environmental exposures, during the fetal and early neonatal life stages, can influence childhood immune system development and alter disease susceptibility later in life. Demonstrating this, epidemiological studies show that the use of antibiotics during pregnancy is associated with an increased risk for allergic asthma in childhood.1 Since antibiotics account for 80% of the medications prescribed during pregnancy, it is increasingly important to understand the connection between prenatal antibiotic exposure and allergic asthma risk. To study this, we recently designed a model in which treatment of pregnant mice with the antibiotic vancomycin resulted in increased severity of allergic asthma in the offspring. We found that antibiotic treatment during pregnancy caused detrimental changes to the maternal gut microbiome, known as microbial dysbiosis, which was then passed on to the offspring.2 In early neonatal life, the gut microbiome interacts very closely with the developing immune system, and we found that the transfer of an antibiotic-altered gut microbiome from mother to offspring programs the immune system to become hyperreactive, which likely increases offspring asthma susceptibility. We would like to further this research by testing possible treatments, such as supplementation with probiotics or immunomodulatory short-chain fatty acids, that can help the maternal gut microbiome recover after exposure to antibiotics during pregnancy.
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.
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.
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.
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:
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 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.
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.
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.
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.
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.
The innate immune system matures early on along with tissue development. In particular, innate lymphoid cells (ILCs, including Natural Killer (NK) cells, already colonize tissues during fetal life and acquire their effector functions already pre-natally. However, exposure to different environmental signals, including microbial infection, can still remodel ILCs and leave permanent epigenetic marks. Our group focuses on delineating transcriptionally and epigenetically the immune functional programs pre-wired during development as well as those emerged and imprinted after exposure to environmental stimuli, in particular persistent virus, thereby setting the threshold of our immune fitness and tolerance to tissue damage. Our aim is to understand the key homeostatic checkpoints, which, once altered, can initiate inflammatory circuits and lead to disease.
Environmental factors such as nutrition but also pollution can significantly influence the health-to-disease transition. The contact of the environment with the human organism, especially at interfaces such as the intestine and the immune system, is of crucial importance. Often, several harmful environmental influences come together to trigger a disease or promote its development. Through our project, we aim to create a better understanding of environmental factors that promote the development of cardiovascular diseases via immunological mechanisms.