PGC-1α调控间充质干细胞耐受凋亡在治疗糖尿病下肢缺血中的机制研究

项目名称： PGC-1α调控间充质干细胞耐受凋亡在治疗糖尿病下肢缺血中的机制研究

项目编号： No.81200614

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 陆德宾

作者单位： 中国人民解放军第三军医大学

项目金额： 23万元

中文摘要： 干细胞移植为糖尿病下肢缺血的治疗提供了新策略，但移植后干细胞的大量凋亡是目前制约其疗效的一个关键问题。我们前期工作发现并报道：上调过氧化物酶增殖体激活受体γ辅激活因子1α(PGC-1α)能增加Bcl-2的表达，有效减少糖尿病缺血诱导的移植干细胞凋亡（已在国外期刊《Diabetes》上发表）。但其具体作用机制尚未明确。通过进一步研究，我们假设：PGC-1α可能与缺血-Bcl-2-线粒体凋亡途径相关的核受体[ERRα和（或）PPARγ]相互作用而调控Bcl-2的表达。因此,本项目拟于在体和离体糖尿病下肢缺血模型上，观察间充质干细胞凋亡以及PGC-1α和ERRα/PPARγ表达的规律；观测阻断ERRα/PPARγ后PGC-1α调控Bcl-2蛋白的表达活性及其对线粒体凋亡途径的影响，揭示PGC-1α抗凋亡作用的分子机制，为减少移植干细胞的凋亡，提高其治疗糖尿病下肢缺血的疗效提供理论依据和新的思路。

中文关键词： 糖尿病；周围血管病变；间充质干细胞；细胞凋亡；过氧化物酶增殖体激活受体γ辅激活因子1

英文摘要： Transplantation of stem cells provides a new strategy for the treatment of diabetic lower limb ischemia. But the apoptosis of a large number of stem cells after the transplantation is one of the key issues which restricts its efficacy now. Our preliminary work discovered and reported: the upregulation of peroxisome proliferation activated receptor gamma coactivator 1 alpha (PGC-1α) could increase the expression of Bcl-2, and effectively reduce the apoptosis of stem cells which was induced by diabetic ischemia after transplantation (published in the international magazine "Diabetes"). But the specific mechanisms of this effect are not yet clear. Through further research, we hypothesized: PGC-1α might interact with the nuclear receptors [ERRα and (or) PPARγ], which was related to the ischemia-Bcl-2-mitochondrial apoptotic pathway, and regulated the expression of Bcl-2. In this project, after transplanted into or cultured in the diabetic ischemia model in vivo or in vitro, the apoptosis of stem cells and the expression levels of PGC-1α and ERRα/PPARγ in mesenchymal stem cells were observed. And after blocking ERRα/PPARγ, the expression of Bcl-2 protein and this effect on the mitochondrial apoptotic pathways in PGC-1α-MSCs were observed. The molecular mechanism of the role of PGC-1α in the resistance to apoptosis ma

英文关键词： diabetes；lower limb ischemia；Mesenchymal stem cells；apoptosis；peroxisome proliferator-activated receptor-γ coact