The role of ApoE in injury-induced neurogenesis

项目摘要 创伤性脑损伤(TBI)后，患者往往出现严重的认知、沟通、 以及行为或情绪的稳定性。在颅脑损伤后，记忆问题通常会发生，这是一些 随同这些受影响地区的发病率。此外，还有一些自发的恢复 脑损伤后，主要由未知的重塑过程发生。已经知道有一段时间了 脑外伤引起海马区新神经元生成增加；然而，这一点的意义并不是 说清楚了。我们最近已经证明，损伤诱导的神经发生至少是部分 与颅脑损伤相关的自发恢复。载脂蛋白E是一种基因，通常以三种不同的亚型出现在 人类和表达的特定亚型可以预测脑损伤后的恢复。我们最近做了 ApoE被认为是海马神经发生的重要调节因子。这个项目的总体目标是 确定载脂蛋白E如何指导脑外伤后损伤诱导的神经发生，并研究其机制 规范这一过程。在具体目标1中，我们将确定载脂蛋白E和两个常见人类 APOE3和APOE4亚型调控损伤诱导的神经发生。对于特定的目标2，我们将使用我们的 最近产生的有花蕾的载脂蛋白E小鼠，有条件地去除祖细胞和 以确定星形胶质细胞在发育和损伤后对神经发生的体内功能。最后， 在特定的目标3中，我们将分析不同载脂蛋白E状态下的损伤诱导神经元，并分析这些 状态影响学习过程中的激活和海马体的整体整合。因此，该项目将 作为翻译研究的基础，旨在利用人类中特定APOE亚型的存在 指导颅脑损伤等严重脑损伤后的修复治疗。

Project Summary 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. ApoE is a gene that commonly occurs in 3 different isoforms in humans and the particular isoform expressed is predictive of recovery following TBI. We have recently identified ApoE as an important regulator of hippocampal neurogenesis. The overall goals of this project are to determine how ApoE directs injury-induced neurogenesis following TBI and to investigate mechanisms that regulate this process. In Specific Aim 1, we will establish how ApoE and two commonly occurring human isoforms, APOE3 and APOE4 regulate injury-induced neurogenesis. For Specific Aim 2, we will use our recently generated floxed ApoE mouse to conditionally ablate ApoE specifically from progenitors and astrocytes to determine its in vivo function on neurogenesis during development and following injury. Finally, in Specific Aim 3, we will analyze injury-induced neurons in a variety of ApoE states and analyze how these states affect activation during learning and overall integration into the hippocampus. This project will therefore serve as the basis for translational studies aimed at using the presence of specific APOE isoforms in humans to direct reparative therapy following serious brain injuries such as TBI.