p38 MAPK in AD-related proinflammatory cytokine up-regulation

描述（由申请人提供）：激活的胶质细胞产生过多的促炎细胞因子是CMS疾病如阿尔茨海默病（AD）的病理生理进展的一个因素。p38丝裂原活化蛋白激酶（MAPK）家族，特别是p38？MAPK是促炎细胞因子产生的重要信号转导调节因子，被确定为外周炎性疾病的体内可药物靶点。然而，我们对p38在体内的潜在参与知之甚少。MAPK，还是密切相关的p38亚型？MAPK，在中枢神经系统促炎细胞因子的产生增加。这个项目将检验p38？在体内，MAPK是ad相关应激源对中枢神经系统促炎细胞因子产生增加的关键贡献者，是一种选择性小分子抑制剂的体内中枢神经系统靶点，未来有可能发展成为改变疾病的治疗药物。具体目的1：我将检验p38pMAPK不参与A？诱导的促炎细胞因子上调和相关的突触功能障碍。我将使用体内ad相关的应激源A？野生型（WT）和p38？敲除（KO）小鼠，并测量海马促炎细胞因子、突触标记蛋白和海马依赖行为缺陷的水平。具体目标2:1将检验p38？MAPK是脑渗透p38 MAPK抑制剂治疗效果的主要贡献者。我会用ad相关的重音，A？输注，WT, p38？MAPK （T106M）和p38？MW01-2-069A-SRM是一种cns渗透和选择性的p38MAPK抑制剂，在存在或不存在MW01-2-069A-SRM的情况下，MAPK（T106M）敲除蛋白（Kl）小鼠对p38MAPK抑制剂具有抗性。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。本研究将描述ad相关p38?活化的体内机制关系。mapk介导的信号转导途径，胶质细胞促炎细胞因子上调，以及相关的神经病理生理，同时为正在进行和未来的ad相关药物开发活动提供更坚实的基础。

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.