Molecular mechanisms of adult neurogenesis following traumatic brain injury

描述（由申请人提供）：每年大约有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换受损的脑组织是一项令人兴奋的新研究方向。尽管内源性成体神经干细胞在脑外伤后可能被隔离在心室下区（SVZ）进行修复和恢复，但这一过程的确切机制尚不清楚。我们最近已经确定，在TBI后成年小鼠SVZ中存在早期神经源性反应（即增殖，存活和迁移）。在缺乏ephrinB3和EphB3受体的情况下，神经源性反应被放大，这与运动功能的改善有关。基于这些初步发现，本研究的目的是研究ephrinB3及其受体是否在脑损伤后发生修饰，以及它们的区域表达如何影响SVZ内稳态以及SVZ衍生npc在损伤环境中的迁移和存活。破坏ephrin/Eph受体相互作用已被证明可以深刻地改变初生SVZ的神经发生（即增殖、迁移和存活）。我们假设，在中度皮质损伤的情况下，SVZ中ephrinBS和/或其受体的下调促进了损伤后的神经发生，这种反应对于TBI后的运动恢复是必要的。本申请的目的1将首先利用Western blot分析、RNase保护实验和免疫组织学技术评估脑外伤后小鼠前脑中ephrinB3及其受体的相对表达水平是否被改变。目的2将通过TBI小鼠模型的功能增益和功能丧失研究，研究ephrinB3及其受体在调节SVZ和受损皮质的增殖、存活和迁移中的作用。Aim 3的研究将确定脑外伤后运动功能的恢复是否取决于svz衍生的npc的招募和动员。利用常驻神经干细胞进行中枢神经系统再生是目前研究的热点。本提案中概述的研究将进一步增强我们对损伤和非损伤大脑中调节神经发生过程的理解。公共卫生相关性：据估计，在一生中，照顾严重创伤性脑损伤幸存者将花费600,000至1,875,000美元。目前的研究旨在了解控制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出新的实验性疗法来治疗脑损伤，并利用成体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.