MSK, RSK and the regulation of excitotoxic cell death and structural plasticity

MSK、RSK 与兴奋性毒性细胞死亡和结构可塑性的调节

• 批准号: 9461131
• 负责人: KARL H OBRIETAN
• 金额: $ 33.69万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9461131
• 关键词: Address; Apoptotic; Architecture; Axon; Biological Assay; Biological Models; Brain region; Brain-Derived Neurotrophic Factor; CREB1 gene; Cell Death; Cell Death Signaling Process; Cell Survival; Cognition Disorders; Couples; Data; Data Reporting; Data Set; Dendrites; Development; Disease; Enzymes; Epilepsy; Epileptogenesis; Event; FRAP1 gene; Foundations; Genetic Transcription; Goals; Hippocampus (Brain); Impaired cognition; Injury; Knockout Mice; Label; Learning; Memory impairment; Mental Depression; MicroRNAs; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Molecular; Morphology; Necrosis; Neurons; Oxidative Stress; Pathologic; Pathway interactions; Pharmacology; Phenotype; Phosphotransferases; Pilocarpine; Play; Process; Publishing; Regulation; Repression; Research; Ribosomal Protein S6 Kinase; Ribosomes; Role; STK11 gene; Signal Pathway; Signal Transduction; Status Epilepticus; Stress; Structure; Synapses; Testing; Therapeutic; Transgenic Mice; Trauma; Traumatic Brain Injury; Work; axon growth; base; cognitive function; design; excitotoxicity; gene function; granule cell; in vivo; inducible gene expression; insight; neuron loss; neuroprotection; novel; novel therapeutic intervention; protein profiling; public health relevance; response; screening; transcription factor

 DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate the roles of the p42/44 Mitogen-Activated Protein Kinase (MAPK) pathway effectors Ribosomal S6 Kinase (RSK) and Mitogen/Stress activated Kinase (MSK) as regulators of excitotoxic cell death and aberrant structural plasticity in the hippocampus. Traumatic brain injury-induced cell death and alterations in synaptic architecture are likely to be underlying events leading to an array of cognitive disorders and the development of epilepsy. Importantly, there is a fundamental unresolved question regarding the signaling events that couple traumatic brain injury to cell death and structural remodeling. Based on recent work by others, our published findings, and the preliminary data reported here, we propose that RSK and MSK are both neuroprotective and couple traumatic brain injury to structural remodeling. Furthermore, we hypothesize that RSK and MSK function through distinct transcriptional and post-translational mechanisms to regulate these processes. To test this hypothesis, we have assembled a novel set of transgenic mice, knockout mice, and an array of screening assays. In Aim 1 we will use the pilocarpine model of status epilepticus (SE) to systematically test the role of MSK as a regulator of SE-induced cell death. We propose that a MSK-CREB signaling cassette plays a key role in cell viability. Specific mechanisms of MSK-CREB- dependent neuroprotection, including the inducible expression of detoxifying enzymes and miRNAs will be examined. In Aim 2 we propose to test the role of RSK in neuroprotection against SE-induced cell death. At a mechanistic level, we will examine the role of RSK as a regulator of pro-apoptotic signaling pathways. In Aim 3, we propose to determine whether MSK and RSK signaling couple traumatic brain injury to aberrant structural plasticity in the hippocampus. A good deal of work has implicated the MAPK pathway as a regulator of activity- dependent dendrite and axon plasticity, however, the role of the MAPK pathway as a regulator of pathophysiologically-induced structural remodeling has not been systematically addressed in vivo. Here we propose to test the hypotheses that RSK stimulates injury-induced axon growth and that MSK couples injury to changes in dendrite structure. The proposed studies will provide novel and definitive data sets, which in turn, could lay the foundation for the development of new therapeutic approaches designed to 'uncouple' SE (and other forms of traumatic brain injury) from its long-term pathophysiological sequelae (e.g., epileptogenesis and cognitive impairments).

 描述（由申请人提供）：本提案的目的是阐明p42/44丝裂原活化蛋白激酶（MAPK）通路效应物核糖体S6激酶（RSK）和丝裂原/应激活化激酶（MSK）作为海马中兴奋性毒性细胞死亡和异常结构可塑性的调节剂的作用。创伤性脑损伤诱导的细胞死亡和突触结构的改变可能是导致一系列认知障碍和癫痫发展的潜在事件。重要的是，关于将创伤性脑损伤与细胞死亡和结构重塑相结合的信号事件，有一个根本的未解决的问题。基于其他人最近的工作，我们发表的研究结果，以及这里报道的初步数据，我们提出RSK和MSK都是神经保护性的，并将创伤性脑损伤与结构重塑结合起来。此外，我们推测RSK和MSK通过不同的转录和翻译后机制来调节这些过程。为了验证这一假设，我们已经组装了一套新的转基因小鼠，敲除小鼠，和一系列的筛选试验。在目的1中，我们将使用癫痫持续状态（SE）的匹鲁卡品模型系统地测试MSK作为SE诱导的细胞死亡的调节剂的作用。我们认为，一个MSK-CREB信号盒在细胞活力中起着关键作用。将研究MSK-CREB依赖性神经保护的具体机制，包括解毒酶和miRNA的诱导表达。在目的2中，我们提出测试RSK在神经保护中对SE诱导的细胞死亡的作用。在一个机制的水平上，我们将研究RSK作为促凋亡信号通路的调节剂的作用。在目标3中，我们提出确定MSK和RSK信号传导是否将创伤性脑损伤与海马结构可塑性异常偶联。大量工作已经暗示MAPK途径作为活性依赖性树突和轴突可塑性的调节剂，然而，MAPK途径作为病理生理学诱导的结构重塑的调节剂的作用尚未在体内系统地解决。在这里，我们建议测试的假设，RSK刺激损伤诱导的轴突生长和MSK夫妇损伤树突结构的变化。拟议的研究将提供新的和明确的数据集，这反过来可以为开发新的治疗方法奠定基础，这些方法旨在将SE（和其他形式的创伤性脑损伤）与其长期病理生理学后遗症（例如，癫痫发生和认知障碍）。