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

非酒精性脂肪性肝病（NAFLD）是西方世界最常见的慢性肝病。这种肝脏疾病导致炎症（非酒精性脂肪性肝炎= NASH）和纤维化，并可能进展为肝硬化，肝衰竭和肝细胞癌。肝淋巴细胞含有自然杀伤（NK）T细胞，并且在患有NASH相关纤维化的人活检中显著改变。由NKT细胞表达的包括CD39（ENTPD-1）的外核苷酸酶（ENTPD）是细胞膜上的酶，催化细胞外ATP/ADP转化为AMP，从而调节由ATP介导的炎症信号传导。本研究的目的是探讨CD39对NAFLD模型中NKT细胞介导的组织损伤的影响。因此，我们的方法将基于以下步骤：（1）将应用鼠模型中的不同饮食研究来模拟人NAFLD的某些方面，并确定NKT细胞在NASH和纤维化进展中的参与。(2)进一步的实验工作，例如用Cd39-null和野生型小鼠的喂养研究和体外测定，将确定NKT细胞上嘌呤能信号传导的潜在机制，从而通过与肝星状细胞的相互作用影响纤维化。(3)将建立转基因小鼠系以研究CD39在NASH和纤维化发展中的NKT细胞特异性功能。这些主题将通过使用细胞和分子生物学方法以及转基因动物模型来处理。这项拟议的研究将有助于了解NAFLD发病机制中的关键信号通路，并可能确定治疗干预的新靶点。

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.