缺血性脑卒中后内源性干细胞参与神经血管重塑的改变和表观遗传学调控研究

项目名称： 缺血性脑卒中后内源性干细胞参与神经血管重塑的改变和表观遗传学调控研究

项目编号： No.81500989

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 魏峥

作者单位： 首都医科大学

项目金额： 17.5万元

中文摘要： 缺血性脑卒中是世界范围内致死致残的重大疾病之一。幸存者大多存在永久感觉运动障碍。本研究致力于研发动员内源干细胞促进感觉运动功能恢复的新疗法。一直以来成体脑内神经元被认为不能新生。直到近年在人成体脑内发现了可分化成神经元和胶质细胞的神经干细胞。动物模型揭示这些神经干细胞在卒中后迅速增生、参与神经新生。而成体干细胞群如何在缺血性脑卒中恢复期及外周刺激康复治疗发挥作用的研究尚少。本研究旨在揭示成体干细胞如何响应卒中发生发展并参与神经功能恢复，着重探讨卒中可能引起的神经干细胞群和骨髓干细胞群的持久改变及对神经血管重塑等的影响。为此，将采用荧光示踪技术特异标记成体干细胞，并进行在体长期追踪研究。将对急性分离的成体干细胞进行转录组学分析，揭开缺血性脑卒中恢复期成体干细胞的继发性改变和分子机制。这将极大促进调动内源干细胞和成体神经血管重塑的治疗研究。

中文关键词： 缺血性脑卒中；神经干细胞；神经新生；表观遗传学；神经血管单元

英文摘要： Ischemic stroke is one of the leading cause of mortality and morbidity in the world. Many survivors of stroke suffer from persistent sensorimotor problems. Our long-term goal is to develop new therapeutics that facilitate sensorimotor functional recovery from ischemic stroke by harnessing the potential of adult brain neural stem cells (NSCs) and peripheral blood bone marrow stem cells (BMSCs). Historically, it had been thought that the adult brain is entirely incapable of replacing neurons lost to injury or disease. However, in recent years, the adult human brain has been discovered to harbor NSCs that can produce both neuron and glia. Experimental data from animal stroke models indicate that these NSCs can respond in the period shortly after injury, increasing cell proliferation and producing new neurons. However, our understanding of how ischemia and peripheral stimulation rehabilitation therapy affect the adult stem cell populations – particularly at the chronic stages of stroke – is largely incomplete. In pursuit of our long-term goal, the objective of this project is to determine how these stem cells respond to stroke from early to chronic stages of recovery. Our central hypothesis is that ischemic stroke induces persistent changes to the NSC and BMSC populations, affecting neurovascular repair for a prolonged period of time. In this proposal, we demonstrate a genetic fate-tracing methodology suitable for following the fate of adult stem cells for long periods of time. Finally, we highlight our ability to acutely isolate NSCs and BMSCs from the mice for modern transcriptome analysis for the purpose of gaining new mechanistic insights into the chronic effect of stroke upon adult stem cells. With these integrated approaches, we propose experimental plans that will determine the chronic effects of ischemic stroke upon the stem cell populations of the adult mice. Such understanding is critical to guide the development of future therapies that involve endogenous stem cells and adult neurovascular repair.

英文关键词： ischemic stroke;neural stem cell;neurogenesis;epigenetics;neurovascular unit