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、沟通以及行为或情绪稳定性方面出现严重障碍。记忆问题通常发生在颅脑损伤后，并伴随着这些受影响区域的一些发病率。此外，脑损伤后有一些自发的恢复，主要是通过未知的重塑过程发生的。众所周知，脑外伤会导致海马区新神经元生成增加；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在一定程度上是与脑外伤相关的自发恢复的基础。因此，促进海马神经发生是为脑外伤患者开发新的治疗方法的一个重要的治疗目标。如果损伤诱导的海马祖细胞的激活对改善功能结果是有用的，促进恢复的一个合理的方法是增加早期前体细胞的增殖。我们最近开发、鉴定和验证了一种新型的转基因小鼠，它允许更昔洛韦诱导的活跃分裂的早期神经前体细胞的消融，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再生是否能改善脑外伤后的预后。在具体目标1中，我们将利用药物手段促进海马神经发生。我们将测试FDA批准的一种通常用于治疗阿尔茨海默病的药物，并确定它是否特别增强损伤后海马区的神经再生。对于特定的目的2，我们将利用时间调节和祖细胞特异性的肿瘤抑制基因PTEN的基因缺失，该基因也特异性地增加海马神经元。对于这两种情况，我们将研究控制性皮质撞击(CCI)损伤后增加神经发生的效果，以确定增强神经发生是否能改善脑外伤后的恢复。

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.