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The Role of ApoE in Injury-Induced Neurogenesis

ApoE 在损伤诱导的神经发生中的作用

基本信息

批准号：
10656489
负责人：
Steven Gerard Kernie
金额：
$ 40.76万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656489
关键词：
Activities of Daily Living Address Adult Affect Alzheimer&apos s Disease American ApoE knockout mouse Apolipoprotein E Area Astrocytes Attenuated Behavioral Behavioral Assay Binding Brain Brain Injuries Cells Cognition Communication Confusion Contralateral Cues Development Dominant-Negative Mutation Emotional Stability Gene Activation Generations Genes Genetic Goals Headache Hippocampus Human Immediate-Early Genes Impaired cognition Impairment Injury Ipsilateral Knock-in Mouse Maps Mediating Memory Memory Loss Methods Microglia Morbidity - disease rate Mus Mutation Neurodegenerative Disorders Neurons Outcome Pattern Population Process Protein Isoforms Public Health Publishing Recovery Regulation Reporter Rest Role Severities Side Signal Transduction TBI Patients TREM2 gene Testing Time Traumatic Brain Injury United States Variant Viral adverse outcome apolipoprotein E-4 brain dysfunction cognitive function cognitive recovery cost dentate gyrus disability genetic signature injured injury recovery memory acquisition mouse model neurogenesis neuron development newborn neuron outcome prediction response to injury therapeutic target transcriptome sequencing translational study

项目摘要

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.

项目摘要创伤性脑损伤（TBI）后，患者通常在认知、交流、和行为或情绪的稳定性。记忆问题通常发生在TBI之后，这些受影响地区的发病率。此外，还有一些自发的恢复在脑损伤后，主要通过未知的重塑过程发生。一段时间以来， TBI增加了海马体中新神经元的产生;然而，这一点的意义并不明显。说清楚了我们先前已经证明，损伤诱导的神经发生至少是一些神经元损伤的基础。与TBI相关的自发恢复。ApoE是一种基因，通常存在于3种不同的亚型中，人和表达的同种型的种类是TBI后恢复的预测。我们已经确定ApoE为海马神经发生的重要调节器。本项目的总体目标是确定如何 ApoE指导TBI后损伤诱导的神经发生，并研究调节这种发生的机制。过程在具体目标1中，我们将定义损伤后ApoE依赖的记忆痕迹，以获得全面的海马体回路改变如何影响整个大脑。对于具体目标2，我们将使用我们最近的产生ApoE 4小鼠以用人ApoE 4有条件地替代ApoE，并证明我们的潜在假设 ApoE 4是负显性的最后，在具体目标3中，我们将阐明其机制通过探索小胶质细胞TREM 2如何调节损伤诱导的神经发生，揭示ApoE在这一过程中的作用通过星形胶质细胞ApoE的结合。因此，该项目将作为翻译研究的基础，利用人类特定ApoE同种型的存在指导严重脑损伤后的修复治疗，如TBI。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Traumatic brain injury-induced fear generalization in mice involves hippocampal memory trace dysfunction and is alleviated by ( R,S )-ketamine.

小鼠创伤性脑损伤引起的恐惧泛化涉及海马记忆痕迹功能障碍，(R,S)-氯胺酮可以缓解这种情况。

DOI：
10.1101/2023.02.24.529876
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
McGowan,JosephineC;Ladner,LilianaR;Shubeck,ClaireX;Tapia,Juliana;LaGamma,ChristinaT;Anqueira-GonzLez,Amanda;DeFrancesco,Ariana;Chen,BrianaK;Hunsberger,HollyC;Sydnor,EzraJ;Logan,RyanW;Yu,Tzong-Shiue;Kernie,StevenG;Denny,
通讯作者：
Denny,

Immune Regulation of Adult Neurogenic Niches in Health and Disease.

健康和疾病中成人神经源性生态位的免疫调节。