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。使用干细胞修复或替换受损的脑组织是一种新的令人兴奋的研究途径。尽管位于脑室下区(SVZ)的内源性成体神经干细胞可能被隔离起来用于脑外伤后的修复和恢复，但这一过程的确切机制尚不清楚。我们最近证实，脑创伤后成年小鼠SVZ存在早期的神经源性反应(即增殖、存活和迁移)。神经源性反应在缺乏EphB3和EphB3受体的情况下被放大，这与运动功能的改善有关。基于这些初步的研究结果，本研究的目的是探讨脑损伤后，脑组织是否会对ewitinB3及其受体进行修饰，以及它们的区域表达如何影响SVZ内的动态平衡以及SVZ来源的神经前体细胞在损伤环境中的迁移和存活。在幼稚的SVZ中，ePhin/Eph受体相互作用的中断已被证明深刻地改变了神经发生(即增殖、迁移和存活)。我们推测，在中度皮质损伤后，下丘脑室旁核中的肾上腺素BS和/或其受体(S)的下调促进了损伤后的神经发生，这一反应是脑创伤后运动恢复所必需的。本应用的目的1将首先通过Western印迹分析、核糖核酸酶保护分析和免疫组织学技术来评估脑损伤后小鼠前脑中ephinB3及其受体(S)的相对表达水平是否发生了改变。目的2通过小鼠脑外伤模型的功能获得和功能丧失的研究，研究肾上腺素B3及其受体(S)在调节SVZ和损伤皮质中的增殖、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依赖于SVZ来源的神经前体细胞的招募和动员。利用常驻神经干细胞再生中枢神经系统有很大的兴趣。这项提案中概述的研究将进一步加强我们对受损和非受损大脑中神经发生调控过程的理解。与公共卫生相关：据估计，在一生中，照顾一名严重脑外伤幸存者的费用在60万美元至187.5万美元之间。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，并利用成人神经干细胞改善遭受头部创伤的患者的功能恢复。

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.