MAP KINASE REGULATION OF MICROGLIAL ACTIVATION

MAP 激酶对小胶质细胞激活的调节

• 批准号: 6639724
• 负责人: NARAYAN R BHAT
• 金额: $ 21.45万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-15 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6639724
• 关键词: CD40 molecule; JUN kinase; MHC class II antigen; cell cell interaction; endotoxins; enzyme activity; enzyme induction /repression; enzyme inhibitors; immunocytochemistry; interleukin 1; interleukin 6; laboratory rat; microglia; mitogen activated protein kinase; mixed tissue /cell culture; myelin; neuroimmunomodulation; nitric oxide synthase; oligodendroglia; phagocytosis; polymerase chain reaction; surface antigens; tumor necrosis factor alpha

Description (From the Applicant's Abstract): Microglia, the principal immune effector cells of the brain, play an important role in the regulation of the immunologic microenvironment within the CNS. They lie dormant until the integrity of the CNS is challenged by injury, infection or disease processes and when chronically activated, secrete a number of inflammatory mediators including cytokines and tissue damaging free radicals as part of the pathogenic mechanism common to a variety of CNS disorders including stroke, Alzheimer's Disease, AIDS dementia and demyelinating diseases such as multiple sclerosis. A mechanistic understanding of the process of microglial activation is, therefore, crucial for devising therapeutic strategies to suppress neuroinflammation. This project tests the hypothesis that signal transduction pathways mediated by members of the mitogen-activated protein kinase (MAPK) family play a key role in microgiial activation and the induction of inflammatory responses. Primary cultures of rat brain microglia wili be used as a model to accomplish the following objectives. The activities and the roles of MAPK cascades (i.e., extracellular signal-regulated kinase or ERK, p38 MAPK and c-Jun N-terminal kinase or JNK) will be investigated in microglia activated in response to endotoxin and receptor (CD40) ligation. The effects of pharmacological inhibitors of MAPKs on the expression of microglial antigens (i.e., MHC class 11, B7 and CD40), cytokines (i.e., TNFa, IL-1, IL-6) and inducible nitric oxide synthase (iNOS) will be determined by immunochemical and RT-PCR techniques. Possible isoforrn-specific roles and down-stream targets of p38 MAPK and JNK in inducing cytokine and iNOS gene expression will be characterized in transient transfection studies using molecular mutants of the kinases along with iNOS and cytokine gene promoter constructs. The suppressive effects of the kinase inhibitors on activation-associated microglial functions; i.e., targeting of oligodendrocytes and myelin phagocytosis will be tested using in vitro models.

描述（来自申请人的摘要）：小胶质细胞，主要的免疫细胞 大脑的效应细胞在调节神经系统中发挥着重要作用 中枢神经系统内的免疫微环境。它们一直处于休眠状态，直到 中枢神经系统的完整性受到损伤、感染或疾病过程的挑战 当长期激活时，会分泌大量炎症介质 包括细胞因子和破坏组织的自由基作为致病因素的一部分 多种中枢神经系统疾病的常见机制，包括中风、阿尔茨海默病 艾滋病痴呆症和多发性硬化症等脱髓鞘疾病。一个 对小胶质细胞激活过程的机制理解是， 因此，对于制定抑制的治疗策略至关重要 神经炎症。该项目测试了信号转导的假设 由丝裂原激活蛋白激酶 (MAPK) 成员介导的途径 家庭在小胶质细胞的激活和诱导中发挥着关键作用 炎症反应。大鼠脑小胶质细胞的原代培养物将用作 实现以下目标的模型。 MAPK 级联的活动和作用（即细胞外 信号调节激酶或 ERK、p38 MAPK 和 c-Jun N 末端激酶或 JNK） 将在响应内毒素而激活的小胶质细胞中进行研究 受体（CD40）连接。 MAPKs 药理学抑制剂对 小胶质细胞抗原（即 MHC 11 类、B7 和 CD40）的表达， 细胞因子（即 TNFa、IL-1、IL-6）和诱导型一氧化氮合酶 (iNOS) 将通过免疫化学和RT-PCR技术来测定。 p38 MAPK 和 JNK 可能的异构体特异性作用和下游靶标 诱导细胞因子和 iNOS 基因表达的特征是瞬时的 使用激酶的分子突变体以及 iNOS 和 细胞因子基因启动子构建体。 激酶抑制剂对激活相关的抑制作用 小胶质细胞功能；即，针对少突胶质细胞和髓磷脂 将使用体外模型测试吞噬作用。