Contribution of neurogenesis to recovery of function following brain trauma

描述(由申请人提供)：尽管经过多年的研究，目前的神经创伤领域无法提供任何治疗方法来解决创伤性脑损伤(TBI)后经常发生的持续性功能丧失问题。干细胞可能在这方面提供了一些潜力。我们对损伤和神经发生之间相互作用的理解主要来自对中风和皮质损伤模型的研究，在这些模型中，病理生理学与实验性脑损伤的差异并不总是使得将数据外推到创伤模型是合适的。目前还没有关于脑室下区(SVZ)中的哪些细胞受到脑外伤影响的信息，以及除了更坚定的祖细胞外，自我更新干细胞的数量是否增加。解决这一问题很重要，因为干细胞数量的增加将表明损伤会在体内诱导信号，使它们能够离开正常的静止状态。如果是这样的话，这将意味着在受伤的大脑中产生新细胞的可能性比之前想象的要大得多。我们提出了四个目标，以开始解决TBI和SVZ之间相互作用的性质。目的1和2：确定颅脑损伤后SVZ的细胞增殖和神经干细胞自我更新是否增加。我们建议同时观察体内(目标1)，使用胸苷标记系统标记损伤前后的分裂细胞，以及体外(目标2)，使用克隆性神经球形成试验。目标3和4：确定增殖祖细胞和表达GFAP的神经干细胞对脑外伤后SVZ细胞增殖和自发行为恢复的贡献。我们建议去除增殖的祖细胞和表达GFAP的干细胞的数量，以评估它们对损伤诱导的SVZ细胞增殖(AIM 3)和功能恢复(AIM 4)的贡献。这个项目与公共卫生界有相当大的相关性，因为我们寻求解决神经源性控制的基本问题，作为确定干细胞促进脑损伤后功能恢复的潜力的第一步。

DESCRIPTION (provided by applicant): Despite years of research, the current neurotrauma field is unable to offer any treatment to address the persistent loss of function that can often occur after a traumatic brain injury (TBI). Stem cells may offer some potential in this regard. Our understanding of the interaction between injury and neurogenesis comes largely from studies on stroke and cortical lesion models where differences in pathophysiology to experimental TBI do not always make it appropriate to extrapolate data to the trauma model. There is currently no information on which cells in the neurogenic subventricular zone (SVZ) are affected by TBI and whether the number of self-renewing stem cells increases in addition to more committed progenitor cells. Resolution of this is important since an increase in stem cell number would indicate that injury induces in vivo cues that allow them to leave their normally quiescent state. If this were to be the case, it would imply a much greater potential for the genesis of new cells in the injured brain than previously thought. We propose four aims to begin to address the nature of the interaction between TBI and the SVZ. Aims 1 and 2: To determine whether cellular proliferation and neural stem cell self-renewal in the SVZ increases following TBI. We propose to look both in vivo (aim 1), using a thymidine-labeling system to label dividing cells before and after injury, and in vitro (aim 2), using a clonal neurosphere-forming assay. Aims 3 and 4: To determine the contribution of proliferating progenitors and GFAP-expressing neural stem cells to increases in SVZ cell proliferation and to spontaneous behavioral recovery following TBI. We propose to ablate the populations of proliferating progenitor and GFAP-expressing stem cells in order to assess their contribution to injury-induced SVZ cell proliferation (aim 3) and to functional recovery (aim 4). This project is of considerable relevance to the public health community as we seek to address fundamental questions on neurogenic control as a first step in determining the potential of stem cells to promote functional recovery after brain trauma.