The role of ApoE injury-induced neurogenesis

 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。载脂蛋白E是一种基因，在人类中通常存在三种不同的亚型，表达的亚型预测脑损伤后的恢复。我们最近发现载脂蛋白E是海马神经发生的重要调节因子。本项目的总体目标是确定载脂蛋白E如何引导脑损伤后损伤诱导的神经发生，并研究调节这一过程的机制。在具体目标1中，我们将确定ApoE和两种常见的人类亚型APOE3和APOE4是如何调控损伤诱导的神经发生的。对于特定的目的2，我们将使用我们最近产生的Floted ApoE小鼠来有条件地去除祖细胞和星形胶质细胞中的ApoE，以确定其在发育和损伤后的神经发生中的体内功能。最后，在具体目标3中，我们将分析损伤诱导的神经元在各种ApoE状态下整合，并分析这些状态如何影响学习过程中的激活和整体整合到海马区。因此，该项目将作为转译研究的基础，旨在利用人类中特定APOE亚型的存在来指导脑损伤等严重脑损伤后的修复治疗。

 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. 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 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 neurons induced to integrate by injury 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.