Natural killer T (NKT)-cell mediated tissue injury is modulated by CD39 in models of nonalcoholic fatty liver disease.

点击翻译按钮获取中文摘要

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in the Western world. This liver disease leads to inflammation (Nonalcoholic Steatohepatitis= NASH) and fibrosis, and may progress to cirrhosis, liver failure and hepatocellular carcinoma. Hepatic lymphocytes contain Natural Killer (NK) T cells and are significantly altered in human biopsies with NASH- related fibrosis. Ectonucleotidases (ENTPDs), including CD39 (ENTPD-1), expressed by NKT cells, are enzymes on the cell membrane catalyzing the conversion of extracellular ATP/ADP to AMP, thereby regulating the inflammatory signaling mediated by ATP. The aim of this proposal is to explore the impact of CD39 on NKT cell mediated tissue injury in models of NAFLD. Hence our approach will be based on the following steps: (1) Different diet studies in murine models will be applied to imitate certain aspects of human NAFLD and to define the involvement of NKT cells in the progression of NASH and fibrosis. (2) Further experimental works, e.g. feeding study with Cd39-null and wild type mice and in vitro assays, will determine underlying mechanisms of purinergic signaling on NKT cells and thus, affecting fibrosis via interaction with hepatic stellate cells. (3) A transgenic mouse line will be created to investigate the NKT cell specific function of CD39 on the development of NASH and fibrosis. These topics will be dealt with by using methods of cell and molecular biology and genetically modified animal models. This proposed research will contribute to the understanding of crucial signaling pathways in the pathogenesis of NAFLD and potentially identify novel targets for therapeutic intervention.