p38 MAPK in AD-related proinflammatory cytokine up-regulation

p38 MAPK 在 AD 相关促炎细胞因子上调中的作用

• 批准号: 7544621
• 负责人: Aaron Scott Borders
• 金额: $ 4.68万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-03 至 2010-05-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544621
• 关键词: Address; Alzheimer' s Disease; Amyloid beta-Protein; Animals; Basic Science; Behavioral; Bioavailable; Biological Sciences; Brain; Central Nervous System Diseases; Class; DLG4 gene; Development; Disease; End Point; Experimental Designs; Exposure to; Failure; Family; Foundations; Functional disorder; Future; Hippocampus (Brain); Human; Inflammatory; Infusion procedures; Knock-out; Knockout Mice; Knowledge; Learning; Lipopolysaccharides; MAPK14 gene; Measurable; Measurement; Measures; Mediating; Medical; Mentors; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinases; Mus; Nature; Neurodegenerative Disorders; Neuroglia; Neurons; Outcome; Peripheral; Production; Protein Isoforms; Proteins; Rate; Research Personnel; Resistance; Signal Transduction; Signal Transduction Pathway; Synapses; Synaptophysin; Testing; Therapeutic; Therapeutic Effect; Tissues; Training; Transcriptional Activation; Treatment outcome; Up-Regulation; base; brain tissue; comparative; cytokine; drug development; experience; genetic regulatory protein; human MAPK14 protein; in vivo; inhibitor/antagonist; insight; post-doctoral training; postsynaptic; pre-doctoral; presynaptic; presynaptic density protein 95; research study; response; small molecule; stressor; therapeutic target

DESCRIPTION (provided by applicant): Excessive proinflammatory cytokine production by activated glia is a contributor to pathophysiology progression in CMS diseases such as Alzheimer's disease (AD). The p38 mitogen activated protein kinase (MAPK) family, especially p38?MAPK, are important signal transduction regulators of proinflammatory cytokine production and were identified as in vivo druggable targets for peripheral inflammatory disorders. However, much less is known about the potential in vivo involvement of p38?MAPK, or the closely related isoform p38?MAPK, in the increased production of CNS proinflammatory cytokines. This project will test the hypothesis that p38?MAPK is a key in vivo contributor to increased CNS proinflammatory cytokine production in response to an AD-relevant stressor, and is an in vivo CNS target for a selective, small molecule inhibitor with potential for future development into disease-altering therapeutics. Specific aim 1: I will test the hypothesis that p38pMAPK does not contribute to A?-induced proinflammatory cytokine up-regulation and associated synaptic dysfunction. I will use an in vivo AD-relevant stressor, A? infusion, in wildtype (WT) and p38? knockout (KO) mice, and measure the hippocampus levels of proinflammatory cytokines, synaptic marker proteins, and hippocampal-dependent behavioral deficits. Specific aim 2:1 will test the hypothesis that p38? MAPK is a major contributor to the therapeutic effects of a brain-penetrant, p38 MAPK inhibitor. I will use an AD-relevant stressor, A? infusion, in WT, p38?MAPK (T106M) and p38?MAPK(T106M) knockin (Kl) mice, which are resistant to p38MAPK inhibitors, in the presence or absence of MW01-2-069A-SRM, a CNS-penetrant and selective p38?.inhibitor. I will measure the same proinflammatory cytokines, synaptic marker proteins, and hippocampal-dependent behavioral deficits as Aim 1. There is a current need for therapeutics for inflammatory-mediated CNS diseases, including AD. This study will characterize the in vivo mechanistic relationships among AD-relevant activation of p38?MAPK-mediated signal transduction pathways, glia proinflammatory cytokine upregulation, and the associated neuropathophysiology, while providing a firmer foundation for on-going and future AD-related drug development campaigns.

描述(由申请人提供)：激活的胶质细胞过度产生促炎细胞因子是导致阿尔茨海默病(AD)等CMS疾病病理生理进展的一个因素。P38丝裂原活化蛋白激酶(MAPK)家族，尤其是p38 MAPK，是促炎症细胞因子产生的重要信号转导调节因子，被认为是治疗外周炎症的体内药物靶点。然而，关于p38MAPK或与之密切相关的p38MAPK亚型在体内参与中枢神经系统促炎症细胞因子产生的潜在可能的研究还很少。本项目将验证这一假说，即p38？MAPK是体内促进中枢神经系统炎性细胞因子产生的关键因素，以应对AD相关应激源，并且是体内中枢神经系统选择性小分子抑制剂的靶点，具有未来发展成为改变疾病的治疗药物的潜力。具体目标1：我将检验p38pMAPK在Aβ诱导的促炎细胞因子上调和相关突触功能障碍中不起作用的假设。我会使用体内AD相关的应激源，A？输液，野生型(WT)和p38？基因敲除(KO)小鼠，并测量海马区促炎症细胞因子、突触标志蛋白和海马区依赖的行为缺陷的水平。具体目标2：1将检验p38？MAPK是一种脑渗透剂p38 MAPK抑制剂的治疗效果的主要贡献者。我会使用与AD相关的压力源，A？将p38MAPK抑制剂耐药的p38MAPK(T106M)和p38MAPK(T106M)敲门(K1)小鼠分别注入或不加入中枢神经系统穿透性选择性p38抑制剂MW01-2-069a-SRM。我将测量与目标1相同的促炎细胞因子、突触标记蛋白和海马区依赖的行为缺陷。目前需要治疗炎症介导的中枢神经系统疾病，包括阿尔茨海默病。本研究将揭示AD相关的p38MAPK信号转导通路激活、神经胶质细胞致炎细胞因子上调和相关神经病理生理之间的体内机制关系，为正在进行的和未来AD相关的药物开发活动提供更坚实的基础。