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、沟通和行为或情绪稳定性方面出现严重残疾。记忆问题通常发生在TBI之后，并且是伴随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TBI可以增加海马体中新神经元的产生;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的基础，至少有一些与TBI相关的自发恢复。因此，海马神经发生的促进代表了为TBI受害者开发新疗法的重要治疗靶点。如果损伤诱导的海马前体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前体细胞的增殖。我们最近开发了一种新的转基因小鼠，其特征在于，并验证了允许更昔洛韦诱导的消融活跃分裂的早期神经祖细胞，使我们能够精确地将任何积极的影响归因于其对神经发生的影响。该项目的总体目标是确定增强神经发生是否改善TBI后的结果。在具体目标1中，我们将使用药理学手段增强海马神经发生。我们将测试一种FDA批准的常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。对于特定目标2，我们将利用时间调节和祖细胞特异性基因缺失的肿瘤抑制基因PTEN，也专门增加海马神经元。对于这两种情况，我们将研究在控制性皮质撞击（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.