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: 9245754
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245754
• 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（由适用提供）：该提案的目的是阐明p42/44丝裂原激活蛋白激酶（MAPK）途径的作用，影响核糖体S6激酶（RSK）和有丝分裂/胁迫激活激活激酶（MSK）作为兴奋性细胞死亡死亡死亡和异常结构可塑性的调节剂。创伤性脑损伤引起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育的潜在事件。重要的是，关于信号事件的基本尚未解决的问题，这些问题使脑部受伤性脑损伤对细胞死亡和结构重塑。根据其他人的最新工作，我们已发表的发现以及此处报告的初步数据，我们建议RSK和MSK既是神经保护性，又是对结构重塑的脑部损伤。此外，我们假设RSK和MSK通过不同的转录和翻译后机制来调节这些过程。为了检验这一假设，我们组装了一组新型的转基因小鼠，基因敲除小鼠和一系列筛选分析。在AIM 1中，我们将使用状态癫痫症（SE）的毛果果模型系统地测试MSK作为SE诱导的细胞死亡的调节剂的作用。我们建议MSK-CREB信号盒在细胞活力中起关键作用。将检查MSK-CREB依赖性神经保护的特定机制，包括排毒酶和miRNA的诱导表达。在AIM 2中，我们建议测试RSK在针对SE诱导的细胞死亡的神经保护中的作用。在机械水平上，我们将研究RSK作为促凋亡信号通路的调节剂的作用。在AIM 3中，我们建议确定MSK和RSK信号传导是否对海马中异常结构可塑性产生创伤性脑损伤。大量工作已经实施了MAPK途径作为活动依赖性树突和轴突可塑性的调节剂，但是，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RSK刺激损伤诱导的轴突生长的假设，并使MSK夫妇受伤对树突结构的变化。拟议的研究将提供新颖和确定的数据集，这反过来又可以从其长期的病理生理后遗症（例如癫痫生成和认知障碍）中开发出旨在从其长期的病理生理后遗症中开发出旨在“脱离” SE（和其他形式的创伤性脑损伤）的新治疗方法的基础。