利用iPSCs技术研究母系遗传糖尿病的内皮细胞功能及其血管损伤修复能力

Seventy-five percent of diabetes patients are dead due to cardiovascular disease-related complications. Endothelial injury-induced vascular homeostasis imbalance plays an important role in diabetes. Incidence rate of the patients with mitochondrial m.3243A>G mutation in Chinese familial type II diabetes is very high. Due to the heterogeneity of mitochondrial mutation, current methods are not convincing to artistically illustrate the mechanisms of mitochondrial mutation-induced diabetes and its associated vascular complications. In this project, the applicants will model maternally inherited diabetes with mitochondrial m.3243A>G mutation by using patient-specific induced pluripotent stem cells (iPSCs). The applicants have proposed three studies: (1) investigating endothelial and mitochondrial dysfunction of patients-specific iPSCs derived endothelial cells (ECs) with mitochondrial m.3243A>G mutation; (2) demonstrating the mechanisms on patient iPSC-ECs dysfunction in term of ROS-NO signaling pathway; (3) evaluating vascular repairing capacity of patient iPSC-ECs. With the success of this project, the applicants will uncover the regulatory mechanisms in the familial diabetes with mitochondrial mutation, set up a drug screening platform, and explore the feasible treatment strategies.

75%的糖尿病患者最终死于心血管类并发症，而内皮功能损伤导致的血管稳态异常在糖尿病中发挥核心作用。线粒体m.3243A>G突变在我国有家族史的II型糖尿病患者中的发生率很高。由于线粒体DNA突变的异质性，现阶段还没有很好的手段来研究线粒体突变引发糖尿病及其血管类并发症的机制。借助本项目团队的知识储备、技术积累、前期实验总结方面的优势，本项目拟利用诱导多能干细胞（iPSCs）技术建立线粒体m.3243A>G突变糖尿病的疾病模型：研究病人来源iPSC-ECs在内皮特性和线粒体功能上的差异；从ROS-NO调控通路的角度探索病人来源iPSC-ECs功能紊乱的调控机制；评估病人iPSC-ECs血管损伤修复能力。本项目的顺利实施能够揭示线粒体DNA突变母系遗传糖尿病的发病机制，建立此类疾病的药物筛选平台，并探索可行的治疗方案。

75%的糖尿病患者最终死于心血管类并发症，而内皮功能损伤导致的血管稳态异常在糖尿病中发挥核心作用。线粒体m.3243A>G突变在我国有家族史的II型糖尿病患者中的发生率很高。由于线粒体DNA突变的异质性，现阶段还没有很好的手段来研究线粒体突变引发糖尿病及其血管类并发症的机制。本项目利用诱导多能干细胞（iPSCs）技术建立不同线粒体m.3243A>G突变率的iPSCs疾病模型，并诱导为内皮细胞（iPSC-ECs）。研究发现m.3243A>G突变异质性的存在不影响iPSCs多潜能性，而对内皮功能进行研究；进一步从ROS-NO调控通路的角度探索病人功能紊乱的调控机制。