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来解决创伤性脑损伤（TBI）后经常发生的持续功能丧失。干细胞可能在这方面提供一些潜力。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病变模型的研究，其中实验性TBI的病理生理学差异并不总是适合将数据外推到创伤模型。目前还没有关于神经源性脑室下区（SVZ）中哪些细胞受到TBI影响的信息，以及除了更多定向祖细胞之外，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表明损伤诱导体内线索，使它们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潜力比以前想象的要大得多。我们提出了四个目标，开始，以解决TBI和SVZ之间的相互作用的性质。目的1和2：确定TBI后SVZ中的细胞增殖和神经干细胞自我更新是否增加。我们建议在体内（目标1），使用胸苷标记系统标记损伤前后的分裂细胞，并在体外（目标2），使用克隆神经球形成试验。目标3和4：确定增殖的祖细胞和表达GFAP的神经干细胞对SVZ细胞增殖增加和TBI后自发行为恢复的贡献。我们建议消融增殖的祖细胞和表达GFAP的干细胞群体，以评估它们对损伤诱导的SVZ细胞增殖（目的3）和功能恢复（目的4）的贡献。这个项目是相当相关的公共卫生界，因为我们寻求解决神经控制的基本问题，作为第一步，在确定干细胞的潜力，以促进脑外伤后的功能恢复。

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.