p38 MAPK in AD-related proinflammatory cytokine up-regulation

描述（由申请人提供）：激活的神经胶质细胞产生的过度促炎细胞因子是CMS疾病如阿尔茨海默病（AD）的病理生理学进展的贡献者。p38丝裂原活化蛋白激酶（MAPK）家族，尤其是p38？MAPK是促炎性细胞因子产生的重要信号转导调节因子，并被鉴定为外周炎性疾病的体内可药用靶标。然而，少得多的是已知的潜在的体内参与p38？MAPK，或密切相关的亚型p38？MAPK在CNS促炎细胞因子产生增加中的作用。该项目将测试的假设，p38？MAPK是体内增加CNS促炎细胞因子产生的关键因素，以响应AD相关应激因子，并且是选择性小分子抑制剂的体内CNS靶标，具有未来开发为改变疾病的治疗剂的潜力。具体目标1：我将检验p38pMAPK对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相关应激源，A？输注，野生型（WT）和p38？敲除（KO）小鼠，并测量促炎性细胞因子、突触标记蛋白和海马依赖性行为缺陷的海马水平。具体目标2：1将测试的假设，p38？MAPK是脑渗透剂p38 MAPK抑制剂的治疗效果的主要贡献者。我将使用与AD相关的应激源A输注，WT，p38？MAPK（T106M）和p38？MAPK（T106M）敲入（KI）小鼠，其在存在或不存在CNS渗透剂和选择性p38？的情况下对p38 MAPK抑制剂具有抗性。抑制剂.我将测量与目标1相同的促炎细胞因子、突触标记蛋白和突触依赖性行为缺陷。目前需要用于炎症介导的CNS疾病（包括AD）的治疗剂。本研究将在体内的机制之间的关系，AD相关的激活p38？MAPK介导的信号转导通路，神经胶质细胞促炎细胞因子上调，以及相关的神经病理生理学，同时为正在进行的和未来的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.