Therapeutic Enhancement of neurogenesis following traumatic brain injury

描述（由申请人提供）：创伤性脑损伤（TBI）后，患者通常在认知、沟通、行为或情绪稳定性方面出现明显的残疾。记忆问题通常发生在创伤性脑损伤之后，并且是这些受影响区域的一些发病率的基础。此外，脑损伤后有一些自发恢复，主要是通过未知的重塑过程发生的。一段时间以来，人们已经知道创伤性脑损伤引起海马中新神经元的增加；然而，这一点的意义尚不清楚。我们最近已经证明，损伤诱导的神经发生至少是部分与TBI相关的自发恢复的基础。因此，促进海马神经发生是开发创伤性脑损伤新疗法的重要治疗靶点。如果损伤诱导的海马祖细胞激活有助于改善功能结果，那么促进恢复的一种合理方法是增加早期祖细胞的增殖。我们最近开发、鉴定并验证了一种新型转基因小鼠，该小鼠允许更昔洛韦诱导主动分裂的早期神经祖细胞消融，使我们能够准确地将促神经发生策略的任何积极作用归因于它们对神经发生的影响。该项目的总体目标是确定增强神经发生是否能改善脑外伤后的预后。在具体目标1中，我们将使用药物手段增强海马神经发生。我们将测试一种fda批准的用于治疗阿尔茨海默病的药物，并确定它是否能特异性地增强损伤后海马体的神经发生。对于Specific Aim 2，我们将利用肿瘤抑制基因PTEN的暂时调控和祖特异性基因缺失，该基因也特异性地增加了海马神经元。对于这两种情况，我们将研究控制性皮质冲击（CCI）损伤后增加神经发生的影响，以确定增强神经发生是否能改善TBI后的恢复。

DESCRIPTION (provided by applicant): Following traumatic brain injury (TBI), patients often develop significant disability in cognition, communication, and behavioral or emotional stability. Problems with memory commonly occur following TBI and underlie some of the morbidity accompanying each of these affected areas. In addition, there is some spontaneous recovery after brain injury that occurs largely by unknown remodeling processes. It has been known for some time that TBI elicits increased generation of new neurons in the hippocampus; the significance of this, however, has not been clear. We have recently demonstrated that injury-induced neurogenesis underlies at least some of the spontaneous recovery associated with TBI. As such, the promotion of hippocampal neurogenesis represents an important therapeutic target for developing new treatments for victims of TBI. If injury-induced activation of hippocampal progenitors is useful at improving functional outcome, one reasonable approach to enhancing recovery would be to increase the proliferation of early progenitors. We have recently developed, characterized, and validated a novel transgenic mouse that allows for ganciclovir-induced ablation of actively dividing early neural progenitors, enabling us to precisely attribute any positive effects of pro-neurogenic strategies to their effects on neurogenesis. The overall goal of this project is to determine whether enhancing neurogenesis improves outcome following TBI. In Specific Aim 1, we will enhance hippocampal neurogenesis using pharmacologic means. We will test an FDA-approved medication commonly used to treat Alzheimer disease and determine whether it specifically enhances neurogenesis in the hippocampus following injury. For Specific Aim 2, we will utilize temporally regulated and progenitor-specific genetic deletion of the tumor suppressor gene PTEN that also specifically increases hippocampal neurons. For both of these, we will study the effects of increasing neurogenesis following controlled cortical impact (CCI) injury to determine whether enhancing neurogenesis improves recovery after TBI.