受体相互作用蛋白1（RIP1）介导的小肠上皮细胞增殖改变在肥胖发生中的作用及机制研究

项目名称： 受体相互作用蛋白1（RIP1）介导的小肠上皮细胞增殖改变在肥胖发生中的作用及机制研究

项目编号： No.81471063

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张秀琴

作者单位： 北京大学

项目金额： 73万元

中文摘要： 肥胖是2型糖尿病和心血管疾病的主要危险因素。流行病学研究指出，过多摄取能量，是肥胖的罪魁祸首。小肠上皮营养物质的吸收是能量摄入的最关键环节。小肠上皮细胞不断地增殖、分化、迁移以及凋亡，维持小肠上皮的结构和吸收功能。我们发现，营养物质可使小肠上皮细胞增殖加快，绒毛变长，吸收能力增加而导致肥胖;阻断肠上皮细胞增殖，可阻止肥胖的发生。受体相互作用蛋白RIP1,是调节细胞凋亡和坏死的重要分子，其功能研究主要集中在免疫、炎症和肿瘤。RIP1是否参与调节小肠上皮细胞的增殖未见报道。我们发现，在肥胖小鼠肠道，RIP1及其泛素化酶cIAP2表达明显增高;而肠上皮细胞特异性RIP1敲除小鼠的体重明显减轻。说明RIP1可能在小肠上皮细胞增殖过程中发挥重要的调节作用。本课题将利用细胞、肠上皮细胞特异性RIP1敲出和转基因小鼠，结合高脂饮食模型，进一步研究RIP1对小肠上皮细胞增殖的调节及在肥胖发生中的作用机制。

中文关键词： 受体相互作用蛋白；小肠上皮细胞增殖；凋亡；小肠吸收；肥胖

英文摘要： Obesity is a major risk factor for type 2 diabetes and cardiovascular disease. Epidemiological studies have suggested that, excessive energy from food intake is the major cause of obesity. Intestinal absorption of nutrients is the initial and key step of energy intake, intestinal epithelial cell through constantly proliferation, differentiation, migration and apoptosis, to maintain the structure and absorptional function of epithelium throughout the lifetime. In previous studies, we found that nutrients could stimulate intestinal epithelial cell proliferation, intestinal villus elongation and increase absorptive capacity during obese development. In contrast, blocking of intestinal epithelial cell proliferation can prevent the occurrence of obesity. Receptor interacting-protein (RIP1), is an important molecular regulator of cell apoptosis and necrosis, the functional study of RIP1 mainly focused on the immune system, inflammation and tumor. Whether RIP1 is involved in the regulation of intestinal epithelial cell proliferation has not been reported. In our study, we found that RIP1 and its ubiquitination enzyme cIAP2 expression were significantly increased in obese mice intestine; intestinal epithelial cell specific RIP1 knockout mice shown significant weight loss, indicating that RIP1 may play an important role in regulating the proliferation of intestinal epithelial cells. In this study, we will use in vitro cell culture, the intestinal epithelial cell specific RIP1 knockout and transgenic mice, and high fat diet induced obese mice model, further investigate the mechanisms that how RIP1 is involved in the regulation of intestinal epithelial cell proliferation, epithelium structure and functional changes in mice and during high fat diet induced obese development.

英文关键词： receptor-interacting protein kinase;intestinal epithelial cell proliferation;apoptosis;intestinal absorption;obesity