SIRT6在低氧性肺动脉高压肺血管重构中的作用及机制研究

项目名称： SIRT6在低氧性肺动脉高压肺血管重构中的作用及机制研究

项目编号： No.81200043

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 喻珊珊

作者单位： 南方医科大学

项目金额： 23万元

中文摘要： 以葡萄糖代谢类型从有氧途径向无氧途径转换为特征的"Warburg效应"在肺动脉高压（PAH）中的重要性越来越受到关注，从能量代谢角度研究PAH的发病机制有助于开发疗效更好的靶向治疗药物。我们前期研究发现能量代谢中的关键分子SIRT6在低氧诱导的人肺动脉平滑肌细胞（HPASMCs）中表达明显下调，提示其可能参与低氧性PAH肺血管重构过程。本项目拟进一步通过基因过表达及RNA干扰等手段研究SIRT6调控HPASMCs增殖与凋亡平衡的作用，明确SIRT6在低氧性PAH肺血管重构中的功能；采用免疫共沉淀、凝胶电泳迁移率变动分析、染色质免疫沉淀和双荧光素酶报告基因等技术，探讨SIRT6是否通过与HIF-1α相互作用并抑制其转录活性进而阻遏下游的HIF-1α-PDK4-PDH通路发挥作用。本项目对阐明低氧性PAH肺血管重构的分子机制具有重要意义，并有望从能量代谢角度为PAH的治疗提供新的靶点。

中文关键词： SIRT6；低氧性肺动脉高压；去乙酰化酶；细胞增殖；细胞凋亡

英文摘要： There is increasing concern about the "Warburg effect" , characterized by the glucose metabolism shifted from aerobic to anaerobic pathways in pulmonary arterial hypertension (PAH), which indicate that energy metabolism is involved in the pathogenesis of PAH and may be a promising target for therapeutic intervention. Our previous study demonstrated that the key molecule in glucose metabolism, SIRT6, is significantly down-regulated in human pulmonary arterial smooth muscle cells (HPASMCs) under hypoxia, suggesting the potential role of SIRT6 in the pulmonary vascular remodeling in hypoxic PAH. In this project, through the methods of overexpression and RNA interference, we are going to study the role of SIRT6 in the maintenance of balance between proliferation and apoptosis in HPASMCs to elucidate the function of SIRT6 in hypoxic PAH pulmonary vascular remodeling. We will further perform co-immunoprecipitation assay, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, and dual luciferase reporter assay to explore the possibility that SIRT6 might play its role via interaction with HIF-1α and repression of transcriptional activity of HIF-1α, followed by the inhibition of the HIF-1α-PDK4-PDH pathway. This project will clarify the pivotal role of SIRT6 in the molecular mechanism of hypoxic PAH,

英文关键词： SIRT6；hypoxic pulmonary arterial hypertension；deacetylase；proliferation；apoptosis