1. The molecular and cell biology of chronic liver diseases.
Here we focus on the exploration of the cellular, molecular and signaling mechanisms of excess scar tissue deposition in fibrosis and cirrhosis (fibrogenesis) and mechanisms of its dissolution (fibrolysis). These studies are linked to translational projects that are aimed at developing non-invasive techniques for monitoring fibrogenesis and fibrolysis in rodents and patients (devising and exploring quantitative imaging agents and novel protein and microparticle markers in serum and plasma: Moreover, we characterize and validate several potential antifibrotic and fibrosis reversal-inducing molecular and cellular therapies. Here, human and experimental in vitro (cell and tissue culture) and vivo models of liver fibrosis, inflammation and oxidative stress are exploited, such as primary and secondary biliary fibrosis, lobular fibrosis and especially non-alcoholic steatohepatitis (NASH), including novel predictive mouse models for primary liver cancer and liver metastasis. In vitro studies are performed with activated hepatic stellate cells, myofibroblasts, Kupffer cells/macrophages, dendritic and myeloid precursor cells, lymphocytes, hepatic progenitor and cancer cells. Specific projects explore modulation of hepatic progenitor/oval cells and macrophages to induce fibrosis reversal and cancer regression. Moreover, in collaboration with nanochemistry groups, organ and cell specific nanoparticles for effective delivery of small molecules and siRNA are evaluated. Finally, the group develops transgenic mice that harbour e.g. myofibroblast specific inducible promoters for the knockdown of potential fibrosis- or immune-system-relevant genes, or transgenic mice for the study of cancer related mechanisms and therapies.
2. The molecular pathogenesis and immunology of chronic intestinal diseases, including celiac disease.
Our prior research has lead to the identification of the celiac disease autoantigen, tissue transglutaminase (TG2), and the establishment of the serum test for antibodies to TG2 which is now used worldwide for the diagnosis of celiac disease. Current studies ocus on the role of TG2 in celiac disease pathogenesis, including the clinical development of a TG2 inhibitor as novel treatment for celiac disease within the CI3 excellence cluster. Several approaches are undertaken to develop a mouse model for celiac disease, including mice with a humanized immune system, to allow the preclinical testing of TG2-inhibition and immune modulatory therapies. We have recently identified amylase trypsin inhibitors (ATIs) of wheat/barley/rye as triggers of nonceliac/non-allergy wheat sensitivity that after oral ingestion uniquely activate intestinal myeloid cells via toll like receptor 4 to cause low level intestinal immune stimulation. How far nutritional ATIs promote intestinal and extraintestinal inflammatory diseases is subject of numerous preclinical and of several clinical studies to begin in autumn of 2016. We also search for serum activity markers of celiac disease and wheat sensitivity. A newly established group in the lab studies the myeloid cells and their modulation in inflammatory bowel diseases, including the search for novel biomarkers of disease activity.
3. Food allergy, the role of allergens as activators of innate immunity, alteration of allergies by environmental factors such as pollution
Apart from amylase-trypsin-inhibitors which are the major inhalative (baker’s asthma) and nutritional allergens in wheat (rye, barley) and at the same time stimulate the central innate immune cell receptor TLR4 (see above), several other proteins appear to activate innate immune cells besides their classical role as allergens. This results in potentiation of their allergenic activity, but also of the allergenicity of other allergens. Moreover, chemical alteration of allergens by environmental factors (pollution), especially nitration by nitric oxide or dimerization by ozone, but also binding to soot particles appear to increase their allergenic or innate immunity stimulating activity. We study these environmental modifications of allergens and their biological effects in cooperation with the Max-Planck-Institute of Chemistry. Within this collaboration we also search for orally active inhibitors of TLR4, mainly derived from herbs, spices and other micronutrients, as an adjunctive therapy for allergies and other intestinal und extraintestinal diseases. In collaboration with the Dermatological Clinic in Mainz and the Division of Gastroenterology in Kiel we develop improved serum diagnostic tests for food allergies and other food sensitivities, by using e.g. confocal endomicrosopy after food challenges and advanced serum proteomics (with the Harvard-Dana Farber Proteomics Core Facility in Boston).
4. The role of macronutrients and the microbiota in intestinal and extraintestinal inflammatory diseases.
This has become a recent research focus. Major emphasis is on common carbohydrates, ATIs in gluten containing cereals, and major lipids, their interaction with the intestinal microbiota and the immune system, and there effect on intestinal and extraintestinal immune diseases. Major diseases assessed in rodent models and planned clinical studies are IBD (IBS), non-alcoholic steatohepatitis (NASH)/type 2 diabetes, and cardiovascular disorders.
5. New Cancer projects and the role and modulation of innate immunity in cancer.
Several projects investigate and target the myeloid cells in various cancers, including metastatic melanoma, primary liver cancer and lung cancer. Her we develop new preclinical models which permit not only mechanistic studies of cancer development, growth and metastasis, but also the testing of novel pharmacological and immunological, as well as the identification of novel serum markers of cancer progression (companion diagnostics for therapy). Many of these studies are interconnected with the projects studying adaptive immunity in cancer with the above mentioned groups and centers.
6. Collaborative research. The above initiatives are not limited to gastrointestinal and liver diseases but are increasingly generating synergies with other clinical departments, such as Dermatology (melanoma, scleroderma, food sensitivities and skin disorders), Cardiology/Center for Thrombosis and Hemostasis/Dept of Medicine 1 (metabolic syndrome/NASH and cardiovascular pathology, liver cancer, NASH, liver fibrosis), Neurology/Psychiatry (e.g., ATIs and autoimmune neurological disease like multiple sclerosis, Alzheimer’s disease), hematology/oncology/Translational Oncology/Pathology (cancer research), Max-Planck-Institute of Chemistry (environment and allergies/inflammation), Institutes in Chemistry/Biology/Max-Planck-Institute for Polymer Sciences (nanoparticular cancer and fibrosis therapy).