Molecular mechanisms of adult neurogenesis following traumatic brain injury

描述（由申请人提供）：每年约有140万美国人遭受创伤性脑损伤（TBI），导致死亡或长期残疾。利用干细胞修复或替代受损的脑组织是一个新的和令人兴奋的研究途径。虽然内源性成体神经干细胞驻留在脑室下区（SVZ）可能会被隔离TBI后的修复和恢复，这一过程的确切机制还没有很好地理解。我们最近已经确定，有一个早期的神经反应（即增殖，存活和迁移）在成年小鼠SVZ TBI后。神经源性反应在缺乏ephrinB 3和EphB 3受体的情况下被放大，这与改善的运动功能相关。基于这些初步的研究结果，本建议的目的是研究ephrinB 3及其受体是否被修改，以应对脑损伤，以及它们的区域表达如何影响稳态SVZ以及迁移和生存SVZ衍生的NPC在受伤的环境。肝配蛋白/Eph受体相互作用的破坏已被证明可以深刻地改变幼稚SVZ中的神经发生（即增殖、迁移和存活）。我们假设，下调ephrinBS和/或其受体（S）在SVZ促进损伤后的神经发生在中度皮质损伤的反应，这种反应是必要的运动恢复TBI后。本申请的目的1将首先通过采用蛋白质印迹分析、RNA酶保护测定和免疫组织学技术来评估在TBI后小鼠前脑中肝配蛋白B3及其受体的相对表达水平是否被改变。目的2将在TBI小鼠模型中使用功能获得和丧失研究来检查ephrinB 3及其受体在调节SVZ和受损皮质中的增殖、存活和迁移中的作用。目标3中的研究将确定TBI后运动功能的恢复是否取决于SVZ衍生的NPC的募集和动员。利用神经干细胞进行中枢神经系统的再生是一个很有意义的研究课题。本提案中概述的研究将进一步增强我们对受伤和未受伤大脑中调节神经发生的过程的理解。公共卫生相关性：据估计，在一生中，照顾严重TBI幸存者的费用将在600，000美元至1，875，000美元之间。目前的研究试图了解脑损伤独特的内源性修复反应的机制，并确定其在长期功能恢复中的作用。我们的最终目标是设计新的实验性疗法来治疗脑损伤，并使用成人神经干细胞改善头部创伤患者的功能恢复。

DESCRIPTION (provided by applicant): Approximately 1.4 million Americans sustain traumatic brain injuries (TBI) each year resulting in death or long-term disability. The use of stem cells to repair or replace damaged brain tissue is a new and exciting avenue of research. Although endogenous adult neural stem cells residing in the subventricular zone (SVZ) may be sequestered for repair and recovery after TBI, the exact mechanism underlying this process is not well understood. We have recently established that there is an early neurogenic response (i.e. proliferation, survival and migration) in the adult mouse SVZ following TBI. The neurogenic response is amplified in the absence of ephrinB3 and EphB3 receptor, which correlates with improved motor function. Based on these preliminary findings, the objective of this proposal is to examine whether ephrinB3 and its receptors are modified in response to brain injury and how their regional expression may influence homeostasis in the SVZ as well as migration and survival of SVZ-derived NPCs in the injured environment. Disruption of ephrin/Eph receptor interactions has been shown to profoundly alter neurogenesis (i.e. proliferation, migration and survival) in the naive SVZ. We hypothesize that down-regulation of ephrinBS and/or its receptor(s) in the SVZ promotes post-injury neurogenesis in response to moderate cortical damage and that this response is necessary for locomotor recovery after TBI. Aim 1 of this application will first evaluate whether the relative expression levels of ephrinB3 and its receptor(s) are modified in the mouse forebrain following TBI by employing Western blot analysis, RNase protection assay and immunohistological techniques. Aim 2 will examine the role of ephrinB3 and its receptor(s) in regulating proliferation, survival and migration in the SVZ and injured cortex using gain- and loss-of-function studies in a mouse model of TBI. Studies in Aim 3 will determine whether recovery of motor function after TBI depends on the recruitment and mobilization of SVZ-derived NPCs. There is great interest in exploiting resident neural stem cells for CNS regeneration. Studies outlined in this proposal will further enhance our understanding of the processes regulating neurogenesis in the injured and non-injured brain. PUBLIC HEALTH RELEVANCE: It is estimated that over a lifetime, it will cost between $600,000 and $1,875,000 to care for a survivor of severe TBI. The current studies seek to understand the mechanisms that govern a unique endogenous repair response to brain injury and to determine its role in long-term functional recovery. Our ultimate goal is to devise novel experimental therapies to treat brain injury and improve recovery of function in patients who sustain head trauma using adult neural stem cells.