Neural Stem Cell Responses to Perinatal Brain Damage

描述（由申请人提供）：我们最近已经确定，在围产期缺氧/缺血（H/I）损伤后，脑室下区（SVZ）有一个由神经干细胞（NSCs）发起的早期再生反应；因此，本提案的目标是建立负责这种适应性变化的分子机制，并确定我们是否可以扩大这种反应。初步数据表明：1)在已知含有NSCs的区域内，SVZ内增殖增加；2)围产期H/I后多电位NSCs丰度有短暂增加；3)体外培养的NSCs保留了对侮辱的记忆；4)这些细胞变化伴随着一些与干细胞维持有关的配体和受体表达的变化。据我们所知，这些是第一个可用的数据，表明中枢神经系统受到任何损伤都会导致多电位神经干细胞数量的变化。因此，该应用的总体假设是，由于干细胞内部的内在变化以及其生态位的外在变化，H/I大脑中干细胞数量的增加。提出了以下具体目标：目标1：确定围产期H/I干细胞反应的大小和动力学；目标2。为了验证脑损伤增加对称的NSC放大细胞分裂的频率的假设；目的3：鉴定围产期H/I后增加神经干细胞数量的分子；目的4：确定H/I后LIF或Notch1受体是否调节NSC数量；目标5。确定神经干细胞丰度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进行中枢神经系统再生非常感兴趣，完成这些研究将增强我们对维持这些前体作为神经干细胞的信号的基本理解，以及哪些信号调节它们在体内的丰度。必须强调的是，目前还没有可用的治疗方法来保护婴儿大脑免受围产期损伤或刺激再生。此外，由于大多数围产期损伤很可能发生在产前，而且这些事件未被发现，因此从这些研究中获得的知识最终可能导致治疗方法，可以用于婴儿，使受损的婴儿大脑能够从其内源性干细胞中正常发育。这种治疗方法显然比移植方法有优势，如果有效，将减少由于围产期脑损伤而导致的认知、运动和情感障碍的发生率和终身。

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.