基于组学特征谱探讨硒蛋白S对糖脂代谢与血管内皮功能的影响及机制

糖脂代谢紊乱及其血管并发症发病机制复杂、尚未全面阐明，临床仍无完全有效的防治策略。硒蛋白S（SelS）的生物学功能具有组织异质性。我们体外研究发现，SelS通过调节内质网应激、氧化应激、凋亡及炎症反应参与糖脂代谢紊乱及血管病变的发生发展，但缺乏体内研究证实。本课题拟在此基础上，聚焦糖脂代谢枢纽和胰岛素作用的主要靶器官—肝脏和脂肪组织，首次构建肝脏/脂肪组织特异性SelS基因敲除小鼠模型，给予正常/高脂饮食，观察小鼠糖脂代谢及内皮功能情况，并利用转录和代谢组学方法，分析肝脏、脂肪以及内皮组织转录本和代谢网络的变化，体内验证课题组前期系列研究成果，同时探索调控肝脏/脂肪组织SelS对糖脂代谢与血管内皮功能影响的其他潜在机制。成果将为SelS生物学功能的体内研究提供可靠的动物模型，丰富糖尿病、脂代谢紊乱及其血管并发症的发病机制，并为SelS作为可针对多重心血管疾病危险因素的新药研发奠定理论基础。

In terms of the complication and the incomplete elucidation of the pathogenesis of glucolipid metabolic disorder and its vascular complications, comprehensive and effective clinical prevention and treatment strategies remain limited. It has been recognized that selenoprotein S (SelS) possesses the characteristic of tissue heterogeneity. Our previous in vitro studies indicated that SelS was involved in the occurrence and development of glucolipid metabolic disorders and vascular diseases by regulating endoplasmic reticulum stress, oxidative stress, apoptosis and inflammatory pathways, but we still lack further validation of in vivo studies. Therefore, in this study, we will focus on liver and adipose tissues, the glucolipid metabolism center and main target organs for insulin. We generate a model of liver/adipose-specific SelS knockout mice for the first time, and then feed them with normal/high fat diet as well as observe the glucolipid metabolism and endothelial functions. Meanwhile, the transcriptomic and metabolomic analysis of liver/adipose tissues and vascular endothelia will be performed to both validate the series of our previous in vitro results and delve into any other potential novel mechanisms of SelS in liver/adipose tissues on glucolipid metabolism and endothelial functions. Our results will offer a promising and reliable in vivo platform for the investigation on the biological function of SelS. Moreover, this study will not only enrich the pathological mechanism of diabetes, lipid metabolic disorders, and their vascular complications, but also provide the fundamental basis for SelS’s research and development as a new drug to target multiple risk factors of cardiovascular diseases.