Mechanisms of hippocampal excitotoxic cell death and structural remodeling

本研究的目的是阐明p42/44丝裂原活化蛋白激酶（MAPK）通路在海马兴奋性细胞死亡和异常结构重塑中的调节作用。创伤性脑损伤诱导的细胞死亡和突触结构的病理生理学改变可能是导致严重的、长期的精神残疾的潜在事件。重要的是，关于调节脑损伤诱导的细胞死亡和结构重塑的信号通路，存在一个根本的未解决的问题。基于最近的工作，我们发表的研究结果，以及这里报道的初步数据，我们提出MAPK通路既具有神经保护作用，又具有兴奋性毒性刺激对结构可塑性的作用。为了检验这些假设并开始鉴定靶向MAPK信号传导的潜在治疗方法，我们组装了一组新的转基因小鼠和一系列筛选测定。在目标1中，我们将研究MAPK通路作为细胞活力调节剂的作用。重要的是，MAPK信号传导对体内神经元存活的精确贡献尚不清楚。沿着这些路线，许多体外研究报道了MAPK信号传导可以促进或减弱神经元死亡，这取决于实验范例。在这个目标中，我们将表征癫痫持续状态（SE）诱导的MAPK通路激活在海马中的时间和细胞类型特异性表达，然后确定MAPK信号传导是否赋予对SE诱导的细胞死亡的保护。我们还将测试MAPK信号调节细胞活力的潜在分子机制。在目标2中，我们将确定MAPK信号传导是否将兴奋毒性应激与异常的结构可塑性偶联。大量的工作已经暗示MAPK通路作为发育依赖性树突和轴突生长的调节剂，然而，MAPK通路在病理生理诱导的结构重塑中的作用尚未得到严格解决。鉴于其强大的重组，重点将放在齿状回的颗粒细胞层。我们的研究将为靶向MAPK信号传导以避免创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。

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.