宫内生长受限（IUGR）可引起成年后代谢综合征发生，其机制在于宫内发育不良造成机体胰岛素抵抗和胰腺发育及功能受损。课题组前期在国家自然基金资助下发现IUGR子代外周组织中NAD+依赖性去乙酰化酶沉默调节蛋白1（Sirtuin1，SIRT1）表达异常。SIRT1是代谢调控的关键基因，它通过抑制未折叠蛋白反应和诱导自噬调控肝脏胰岛素敏感性和胰腺发育和胰岛素分泌从而调节糖脂代谢。本课题在前期研究基础上，通过体内体外实验系统研究IUGR子代发育成长过程中，肝脏和胰腺中SIRT1的表观遗传修饰变化和下游信号通路因子的改变，如何影响未折叠蛋白反应通路和自噬、最终损害肝脏胰岛素敏感性和β细胞发育及分泌功能；探讨SIRT1过表达和激活的干预作用。研究结果有助于深入理解IUGR与代谢综合征的分子联系，为进一步认识胎儿起源的成人疾病，预防和减少代谢综合征的发生提供理论依据和实验基础。

Intrauterine growth restriction (IUGR) leads to the development of adulthood metabolic syndrome, which originated from organism insulin resistance and impaired development of the pancreas caused by poor intrauterine growth. The results of our preliminary research funded by the National Natural Science Foundation, indicated that the expression of deacetylase Sirtuin1(SIRT1) was disturbed in multiple peripheral tissues of IUGR offspring. NAD+ dependent deacetylase SIRT1 acts as a key factor for the regulation of glucose and lipid metabolism by inhibiting unfolded protein response and inducing autophagy which then impact hepatic insulin sensitivity and development and insulin secretion of the pancreas.Based on previous studies, this project will investigate the epigenetic changes in the SIRT1 and the downstream signaling pathways and subsequent impact on unfolded protein response and autophagy in the hepatic and pancrea, then analyze the impact on hepatic insulin sensitivity and the development and secretory function of β cell. Further study will focus on the intervention effect of SIRT1 overexpression or activator. The study above will elucidate the pathogenesis of fetal origins of adult metabolic syndrome, provide theoretical basis and experiment evidence for further investigation of fetal origins of adult disease, and for preventing and reducing the occurrence of metabolic syndrome.