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。我们以前已经证明，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 人类和表达的这种亚型预示着脑外伤后的恢复。我们已确定载脂蛋白E为 海马神经发生的重要调节因子。该项目的总体目标是确定如何 载脂蛋白E指导脑外伤后损伤诱导的神经发生并研究其调节机制 进程。在具体目标1中，我们将定义损伤后载脂蛋白E依赖的记忆痕迹，以获得全面的 改变的海马体回路如何影响整个大脑的图片。对于特定的目标2，我们将使用我们最近的 产生载脂蛋白E4小鼠，有条件地用人载脂蛋白E4取代载脂蛋白E，并证明我们的基本假设 载脂蛋白E4起着显性否定的作用。最后，在具体目标3中，我们将阐明这一机制 探讨小胶质细胞TREM2如何调控载脂蛋白E在损伤诱导的神经发生中的作用 通过与星形细胞载脂蛋白E结合。因此，该项目将作为翻译研究的基础，旨在 利用人类特定载脂蛋白E亚型的存在指导严重脑损伤后的修复治疗 伤情，如脑外伤。

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 previously 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 kind of isoform expressed is predictive of recovery following TBI. We have 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 define the ApoE-dependent memory trace after injury to get a comprehensive picture of how altered hippocampal circuitry affects the entire brain. For Specific Aim 2, we will use our recently generated ApoE4 mouse to conditionally replace ApoE with human ApoE4 and prove our underlying hypothesis that ApoE4 functions as a dominant negative. Finally, in Specific Aim 3, we will elucidate the mechanism underlying ApoE’s role in injury-induced neurogenesis by exploring how microglial TREM2 regulates this process via binding of astrocytic ApoE. 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.