Reactive neural stem cells in perinatal brain damage

描述(由申请人提供)： 该项目的总体长期目标是确定脑损伤对内源性神经干细胞(NSCs)的影响。具体地说，这项建议旨在确定这些神经干细胞对围产期缺氧/缺血(H/I)脑损伤的急性反应。一旦明确，这种反应可能为预防围产期缺氧缺乏症的后果，如脑性瘫痪、智力低下和其他一系列神经疾病提供潜在的治疗靶点。众所周知，神经干细胞终生以静止的细胞群存在于脑室下区(SVZ)。这些细胞在体外和体内都可以用特定的生长因子诱导增殖。我们观察到，缺氧缺血后SVZ分离培养的NSCs更为丰富，因此，近期的目标是明确围产期缺氧/缺氧对SVZ NSCs的急性影响。我的中心假设是，围产期H/I将NSCs招募到更多的增殖状态，从而扩大了总人口。我将测定缺氧/缺血对SVZ生长因子及其受体水平的影响，以及缺氧/缺血后神经干细胞对这些生长因子的量效关系，以及缺氧/缺血对神经干细胞增殖动力学和分裂方式的影响。这些实验可能为围产期脑损伤的治疗策略确定一个新的靶点。

DESCRIPTION (provided by applicant): The general long-term goal of this project is to identify the effects of brain injury on endogenous neural stem cells (NSCs). Specifically this proposal aims to identify the acute response of these NSCs to a perinatal hypoxic/ischemic (H/I) brain insult. Once defined, this response could provide a potential therapeutic target for preventing consequence of perinatal H/I such as cerebral palsy, mental retardation, and a spectrum of other neurological disorders. NSCs are known to reside as a quiescent population of cells in the subventricular zone (SVZ) throughout life. These cells can be induced to proliferate both in vitro and in vivo with specific growth factors. We have observed that NSCs are more abundant in dissociated cultures of the SVZ after H/I; therefore, the immediate goal is to define the acute effects of perinatal H/I on SVZ NSCs. My central hypothesis is that perinatal H/I recruits NSCs to a more proliferative state, thereby expanding the total population. I will determine the effect of H/I on levels of growth factors and their receptors in the SVZ as well as the dose-response of NSCs to these growth factors after H/I. I will also determine the effects of H/I on the proliferation kinetics and mode of division of NSCs. These experiments can potentially identify a novel target for therapeutic strategies in perinatal brain injury.