Therapeutic Enhancement of neurogenesis following traumatic brain injury

创伤性脑损伤后神经发生的治疗增强

• 批准号: 8596011
• 负责人: Steven Gerard Kernie
• 金额: $ 20万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596011
• 关键词: Ablation; Activities of Daily Living; Affect; Alzheimer' s Disease; American; Animal Model; Area; Behavioral; Blast Injuries; Brain Injuries; Brain Part; Cognition; Cognitive; Communication; Confusion; Emotional; FDA approved; Ganciclovir; Generations; Genetic; Goals; Headache; Hippocampus (Brain); Impaired cognition; Individual; Injury; Manufactured football; Mediating; Memory; Memory Loss; Military Personnel; Morbidity - disease rate; Neurons; Outcome; PTEN gene; Patients; Pharmaceutical Preparations; Play; Process; Public Health; Recovery; Recurrence; Regulation; Role; Simplexvirus; Specific qualifier value; Specificity; Sports; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Traumatic Brain Injury; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; Validation; adverse outcome; base; behavior test; controlled cortical impact; cost; disability; donepezil; functional outcomes; improved; injured; knowledge of results; nerve stem cell; nestin protein; neurogenesis; novel; progenitor; public health relevance; therapeutic target; tool

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.

描述（由申请人提供）：创伤性脑损伤（TBI）后，患者通常会在认知、沟通、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 TBI 后，并且是这些受影响区域的一些发病的基础。此外，脑损伤后存在一些自发恢复，这主要是通过未知的重塑过程发生的。一段时间以来，人们就知道创伤性脑损伤会导致海马体中新神经元的产生增加。然而，其意义尚不清楚。我们最近证明，损伤诱导的神经发生至少是与 TBI 相关的部分自发恢复的基础。因此，促进海马神经发生是为 TBI 患者开发新疗法的重要治疗目标。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就是增加早期祖细胞的增殖。我们最近开发、表征和验证了一种新型转基因小鼠，它允许更昔洛韦诱导活跃分裂的早期神经祖细胞的消融，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发生是否可以改善 TBI 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 FDA 批准的一种常用于治疗阿尔茨海默病的药物，并确定它是否能特异性增强损伤后海马体的神经发生。对于特定目标 2，我们将利用肿瘤抑制基因 PTEN 的时间调节和祖细胞特异性基因删除，该基因删除也特异性地增加海马神经元。对于这两者，我们将研究受控皮质冲击 (CCI) 损伤后增加神经发生的影响，以确定增强神经发生是否可以改善 TBI 后的恢复。