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。ApoE是一种基因，通常在人类中以3种不同的亚型存在，表达的亚型类型可预测TBI后的恢复。我们最近发现ApoE是海马神经发生的重要调节因子。该项目的总体目标是确定ApoE如何指导TBI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APOE 3和APOE 4如何调节损伤诱导的神经发生。对于特异性目标2，我们将使用我们最近产生的floxed ApoE小鼠特异性地从祖细胞和星形胶质细胞中条件性消融ApoE，以确定其在发育期间和损伤后对神经发生的体内功能。最后，在具体目标3中，我们将分析在各种ApoE状态下损伤诱导整合的神经元，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中。因此，该项目将作为翻译研究的基础，旨在利用人类特定APOE亚型的存在指导严重脑损伤（如TBI）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.