Neural Stem Cell Responses to Perinatal Brain Damage

描述(由申请人提供)：我们最近证实，在围产期缺氧/缺血(H/I)损伤时，脑室下区(SVZ)中的神经干细胞(NSCs)启动了早期再生反应；因此，本建议的目标是建立导致这种适应性变化的分子机制，并确定我们是否可以放大这种反应。初步数据表明：1)在已知包含神经干细胞的区域内，SVZ内的增殖增加；2)围产期缺氧/缺血后多潜能神经干细胞的丰度一过性增加；3)体外放置的NSCs保留了对损伤的记忆；4)这些细胞变化伴随着与干细胞维持有关的几种配体和受体表达的变化。据我们所知，这些是第一批可获得的数据，表明由于对中枢神经系统的任何侮辱，多潜能神经干细胞的数量发生了变化。因此，这一应用的总体假设是，由于干细胞内部的内在变化以及它们的利基的外部变化，H/I脑中的干细胞数量增加。提出了以下具体目标：目的1：确定干细胞对围产期H/I反应的大小和动力学；目的2.检验脑损伤增加对称性NSC分裂频率的假设；目标3：确定围产期H/I后放大神经干细胞数量的分子；目标4：确定LIF或Notch1受体是否调节H/I后NSC数量；目标5.确定神经干细胞数量的增加是直接影响细胞的结果还是干细胞生态位变化的结果。由于人们对利用干细胞再生中枢神经系统非常感兴趣，这些研究的完成将加强我们对维持这些前体细胞作为神经干细胞的信号以及哪些信号调节它们在体内的丰度的基本理解。必须强调的是，目前还没有可用的治疗方法来保护婴儿的大脑免受围产期的侮辱或刺激再生。此外，由于大多数围产期侮辱很可能发生在产前，而且此类事件发生时未被发现，从这些研究中获得的知识最终可能导致可以对婴儿进行治疗，使受损的婴儿大脑能够从其内源性干细胞正常发育。这种疗法显然比移植方法有优势，如果有效，将减少因围产期脑损伤而发生的认知、运动和情感障碍的发生率和终生残疾。

DESCRIPTION (provided by applicant): We have recently established that there is an early regenerative response initiated by the neural stem cells (NSCs) in the subventricular zone (SVZ) in response to a perinatal hypoxic/ischemic (H/I) insult; therefore, the goals of this proposal are to establish the molecular mechanisms responsible for this adaptive change and to determine whether we can amplify this response. Preliminary data indicate that: 1) there is increased proliferation within the SVZ within the region that is known to contain the NSCs; 2) there is a transient increase in the abundance of multipotential NSCs after perinatal H/I; 3) NSCs placed in vitro retain a memory of the insult; and 4) these cellular changes are accompanied by changes in the expression of several ligands and receptors that have been implicated in stem cell maintenance. To our knowledge, these are the first available data demonstrating that there is a change in the numbers of multipotential NSCs as a consequence of any insult to the CNS. Consequently, the overall hypothesis of this application is that there is an increase in the number of stem cells in the H/I brain as a consequence of both intrinsic changes within the stem cells as well as extrinsic changes to their niche. The following specific aims are proposed: Aim 1: To determine the magnitude and kinetics of the stem cell response to perinatal H/I; Aim 2. To test the hypothesis that brain damage increases the frequency of symmetrical NSC amplifying cell divisions; Aim 3: To identify the molecules that amplify neural stem cell numbers after perinatal H/I; Aim 4: To determine whether LIF or Notch1 receptors regulate NSC numbers after H/I; Aim 5. To determine whether the increased abundance of neural stem cells is a consequence of a direct effect on the cells or whether this increase is a result of changes to the stem cell niche. As there is great interest in exploiting stem cells for CNS regeneration, completion of the proposed studies will enhance our fundamental understanding of the signals that maintain these precursors as neural stem cells and which signals regulate their abundance in vivo. It must be emphasized that at the present time, there are no therapies available to protect the infant brain from perinatal insults or stimulate regeneration. Moreover, as it is likely that the majority of perinatal insults occur during the antenatal period and that such events occur undetected, the knowledge obtained from these studies could eventually lead to therapeutics that could be administered to infants to enable the damaged infant brain to develop normally from its endogenous stem cells. Such therapies would clearly have advantages over transplantation approaches, and if effective would decrease the incidence and life long cognitive, motor and emotional handicaps that occur as a result of perinatal brain damage.