Mechanisms of hippocampal excitotoxic cell death and structural remodeling

海马兴奋性毒性细胞死亡和结构重塑的机制

基本信息

批准号：
7774848
负责人：
KARL H OBRIETAN
金额：
$ 37.2万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7774848
关键词：
Acute Address Apoptotic Architecture Attenuated BCL2L11 gene Biological Assay Brain Injuries Cell Death Cell Survival Cells Cessation of life Cognition Disorders Complement Complex Couples Data Data Reporting Dendrites Epilepsy Event Genetic Models Goals Growth Hippocampus (Brain)In Vitro Maps Mediator of activation protein Mitogen-Activated Protein Kinases Modeling Molecular Molecular Genetics Monitor Mouse Strains Necrosis Neuronal Injury Neurons Oxidative Stress Pathway interactions Phosphotransferases Population Process Psyche structure Publishing Regulation Relative (related person)Reporting Research Resistance Role Screening procedure Seizures Signal Pathway Signal Transduction Status Epilepticus Stimulus Stress Synapses Testing Tetanus Helper Peptide Tetracyclines Therapeutic Transgenic Mice Traumatic Brain Injury Vertebral column Work axon growth axonal sprouting base cell type dentate gyrus disability excitotoxicity granule cell in vivo insight neuronal survival novel research study response

项目摘要

The goal of this proposal is to elucidate the role of the p42/44 mitogen-activated protein kinase (MAPK) pathway as a regulator excitotoxic cell death and aberrant structural remodeling in the hippocampus. Traumatic brain injury-induced cell death and pathophysiological alterations in synaptic architecture are likely to be underlying events leading to profound, long-term, mental disability. Importantly, there is a fundamental unresolved question regarding the signaling pathway(s) that regulate brain injury-induced cell death and structural remodeling. Based on recent work by others, our published findings, and the preliminary data reported here, we propose that the MAPK pathway is both neuroprotective and couples excitotoxic stimuli to structural plasticity. To both test these hypotheses and begin to identify potential therapeutic approaches to target MAPK signaling, we have assembled a novel set of transgenic mice and an array of screening assays. In Aim 1, we will examine the role of the MAPK pathway as a regulator of cell viability. Importantly, the precise contribution of MAPK signaling to neuronal survival in vivo is not known. Along these lines, a number of in vitro studies have reported that MAPK signaling can either contribute to or attenuate neuronal death, depending on the experimental paradigm. In this aim, we will characterize the temporal and cell-type specific expression of status epilepticus-(SE) induced MAPK pathway activation in the hippocampus, and then determine whether MAPK signaling confers protection against SE-induced cell death. We will also test potential molecular mechanisms by which MAPK signaling modulates cell viability. In Aim 2, we will determine whether MAPK signaling couples excitotoxic stress to aberrant structural plasticity. A good deal of work has implicated the MAPK pathway as a regulator of developmentally-dependent dendrite and axon growth, however, the role of the MAPK pathway in pathophysiologically-induced structural remodeling has not been rigorously addressed. Given its robust reorganization, emphasis will be placed on the granule cell layer of the dentate gyrus. Our research will provide insights into the potential therapeutic value of targeting MAPK Signaling to avert traumatic brain injury cell-death and aberrant structural plasticity.

该提案的目的是阐明p42/44丝裂原激活蛋白激酶（MAPK）途径作为调节剂在海马中的调节剂兴奋性细胞死亡和异常结构重塑的作用。创伤性脑损伤引起的细胞死亡和突触结构中的病理生理改变可能是导致深远，长期精神残疾的基本事件。重要的是，关于调节脑损伤引起的细胞死亡和结构重塑的信号通路的基本未解决的问题。基于其他人的最新工作，我们已发表的发现以及此处报告的初步数据，我们建议MAPK途径既是神经保护症，又是偶然的兴奋性刺激对结构可塑性。为了测试这些假设，并开始确定目标MAPK信号的潜在治疗方法，我们组装了一组新型的转基因小鼠和一系列筛选分析。在AIM 1中，我们将研究MAPK途径作为细胞活力的调节剂的作用。重要的是，MAPK信号对体内神经元存活的精确贡献尚不清楚。沿着这些线路，许多体外研究报告说，根据实验范式，MAPK信号传导可以导致或减弱神经元死亡。在此目标中，我们将表征状态 - 癫痫持续状态（SE）诱导的MAPK途径激活的时间和细胞类型的特异性表达，然后确定MAPK信号是否赋予了针对SE诱导的细胞死亡的保护。我们还将测试MAPK信号传导调节细胞活力的潜在分子机制。在AIM 2中，我们将确定MAPK信号伴侣是否对异常结构可塑性进行兴奋性毒性应力。大量工作已将MAPK途径作为发展依赖性树突和轴突生长的调节剂，但是，MAPK途径在病理生理诱导的结构重塑中的作用尚未被严格解决。鉴于其强大的重组，将重点放在齿状回的颗粒细胞层上。我们的研究将为靶向MAPK信号传导以避免外伤性脑损伤细胞死亡和异常结构可塑性的潜在治疗价值提供见解。