孕期缺氧对胎肝发育及NAFLD的胎源性机制研究

Epidemiological investigations have showed that the proportion of nonalcoholic fatty liver disease (NAFLD) has a highly prevalent and increasing tendency, and also has developmental origin.Researches have indicated that prenatal hypoxia(PH) may enhance susceptibility to intrauterine growth retardation(IUGR) and adult metabolic syndrome, and the mechanism is relative to the alterations of insulin resistance(IR), renin-angiotensin system (RAS) and its regulatory functions. In our previous studies,we have discovered that PH may induce IUGR, affect the fetal development by decreasing the ratio of liver weight and fetal body weight, also change the hepatic RAS and its regulatory metabolic functions. However, information on effects of PH on fetal liver development and offspring NAFLD regulation via RAS is very limited. This project will use fetal rat and cell hypoxic models, We will determine impact of prenatal hypoxia on RAS functions and programmed NAFLD problems, to determine key point and possible intrauterine programming mechanism of insulin signaling pathway regulated by RAS in the fetal liver in development and progression of NAFLD in the lab animals,tissues and organs, and cell levels. The results will provide information on the influence of prenatal hypoxia on possible abnormal development of fetal liver RAS as well as its impact on formation of NAFLD in fetal origins. The project will provide new insight on special intrauterine fetal rat and cell hypoxic models and intrauterine programming mechanism, the data gained will assist to study mechanism, early intervention and prevention of measures of NAFLD caused by fetal original factors,and further looking for targets and providing important experimental and theory basis.

流行病学调查显示：非酒精性脂肪肝(NAFLD)发病率逐年上升且有宫内发育起源。研究表明：孕期缺氧(PH)可致胎儿宫内生长受限(IUGR)及子代代谢综合征易感，其机制与胰岛素抵抗、肾素血管紧张素系统(RAS)及其调控功能有关。我们前期研究：PH可致IUGR、胎儿发育不良等，但PH对胎肝发育及子代NAFLD易感性的关联研究及机制探讨鲜有报道。据此提出假说：PH可致胎肝RAS宫内编程改变并以此调控胰岛素信号通路等参与并介导PH所致的胎儿发育异常及胎源性NAFLD发生。为验证此，本项目以在体动物和离体细胞缺氧模型为基础，宫内胎儿-子代为研究对象，RAS发育为切入点，孕期缺氧对子代NAFLD易感性的RAS调控机制为主线，阐明胎肝RAS调控的胰岛素信号通路在胎源性NAFLD中的关键地位及机制。研究以独特的表观遗传学机制为新视点，为胎源性NAFLD的机制研究、早期干预及治疗寻找新靶点等提供重要理论依据。

流行病学调查显示：非酒精性脂肪肝(NAFLD)发病率逐年上升且有宫内发育起源。研究表明：孕期缺氧(PH)可致胎儿宫内生长受限(IUGR)及子代代谢综合征易感，其机制与胰岛素抵抗、肾素血管紧张素系统(RAS)及其调控功能有关。我们前期研究：PH可致IUGR、胎儿发育不良等。通过本项目研究发现，PH还与胎肝发育及子代NAFLD易感性相关。研究结果显示，PH可致胎肝RAS宫内编程改变并以此调控胰岛素信号通路等参与并介导PH所致的胎儿发育异常及胎源性NAFLD发生。本项目以在体动物和离体细胞缺氧模型为基础，宫内胎儿-子代为研究对象，RAS发育为切入点，孕期缺氧对子代NAFLD易感性的RAS调控机制为主线，阐明了胎肝RAS调控的胰岛素信号通路在胎源性NAFLD中的关键地位及机制。研究为胎源性NAFLD的机制研究、早期干预及治疗寻找新靶点等提供重要理论依据。