Glia Maturation Factor in CNS Inflammation

中枢神经系统炎症中的神经胶质成熟因子

• 批准号: 6896541
• 负责人: ASGAR ZAHEER
• 金额: $ 34.11万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6896541
• 关键词: Alzheimer' s disease; JAK kinase; Parkinson' s disease; antigen presenting cell; astrocytes; biological signal transduction; central nervous system; experimental allergic encephalomyelitis; gene expression; genetically modified animals; glia; inflammation; laboratory mouse; microglia; mitogen activated protein kinase; multiple sclerosis; oligodendroglia; tissue /cell culture

DESCRIPTION (provided by applicant): Elucidation of the molecular mechanisms that regulate inflammation in the central nervous system (CNS) is critical to our understanding of a broad spectrum of diseases, including multiple sclerosis, Alzheimer's, and Parkinson's. These diseases are responsible for significant morbidity and mortality, and new prevention and treatment approaches are urgently needed. This proposal builds on our recent finding that glia maturation factor (GMF), a highly conserved protein unique to the brain, serves as an important immune modulator by promoting the production and secretion of pro-inflammatory cytokines leading to the activation of microglia, the antigen presenting cells in the brain. The Human Genome Sequence Consortium has identified the gene of GMF in chromosome 14. In this proposal, we will study experimental autoimmune encephalomyelitis (EAE), the standard animal model for multiple sclerosis, with the hypothesis that GMF contributes to the pathogenesis of EAE. This research will include investigations on the already available GMF knockout mice, wild type mice, and GMF transgenic mice (in the final stages of development) in which GMF transgene will be reintroduced in GMF knockout mice under the influence of astrocyte-specific GFAP promoter. This will provide, for the first time, a unique opportunity to study the pathogenesis of EAE in the contrasting settings of no GMF, normal amount of GMF, and high expression of GMF. AIM I: To study the effects of GMF on the two major signal transduction cascades involved in CNS inflammation and immune processes, namely, the p38 MAP kinase and JAK/STAT pathways. We will utilize cultured brain cells, astrocytes, microglia and oligodendroglia, derived from GMF knockout versus wild type mice. AIM II: To study the role of GMF in the pathophysiology of EAE and to establish that the absence of GMF mitigates the severity of the disease. (A) GMF knockout and wild type mice will be challenged with the proper antigen to induce EAE. The development and the histopathology of the brain and spinal cord at various stages of the disease will be compared. (B) To evaluate the expression profiles of cytokines and the free radical generating mediators during the progression of EAE in the brain, spinal cord and in isolated mononuclear cells. Knowledge obtained from this study can also be applied to degenerative diseases of the brain where microglial activation plays an important role, such as Alzheimer's and Parkinson's.

描述（由申请人提供）：阐明调节中枢神经系统（CNS）炎症的分子机制对于我们了解多种疾病至关重要，包括多发性硬化症、阿尔茨海默病和帕金森病。这些疾病导致很高的发病率和死亡率，迫切需要新的预防和治疗方法。该提议建立在我们最近的发现之上，即神经胶质成熟因子（GMF）是大脑特有的一种高度保守的蛋白质，通过促进促炎细胞因子的产生和分泌，从而导致小胶质细胞（大脑中的抗原呈递细胞）的激活，充当重要的免疫调节剂。人类基因组序列联盟已在 14 号染色体上鉴定出 GMF 基因。在本提案中，我们将研究实验性自身免疫性脑脊髓炎 (EAE)（多发性硬化症的标准动物模型），并假设 GMF 与 EAE 的发病机制有关。这项研究将包括对现有的 GMF 敲除小鼠、野生型小鼠和 GMF 转基因小鼠（处于开发的最后阶段）的研究，其中在星形胶质细胞特异性 GFAP 启动子的影响下，GMF 转基因将重新引入 GMF 敲除小鼠中。这将首次提供一个独特的机会，在无 GMF、正常量 GMF 和高 GMF 表达的对比环境中研究 EAE 的发病机制。目的一：研究GMF对参与中枢神经系统炎症和免疫过程的两个主要信号转导级联，即p38 MAP激酶和JAK/STAT通路的影响。我们将利用来自 GMF 敲除小鼠与野生型小鼠的培养脑细胞、星形胶质细胞、小胶质细胞和少突胶质细胞。目标 II：研究 GMF 在 EAE 病理生理学中的作用，并确定缺乏 GMF 可减轻疾病的严重程度。 (A) GMF 敲除小鼠和野生型小鼠将受到适当抗原的攻击以诱导 EAE。将比较疾病各个阶段的大脑和脊髓的发育和组织病理学。 (B) 评估脑、脊髓和分离的单核细胞中 EAE 进展过程中细胞因子和自由基生成介质的表达谱。从这项研究中获得的知识也可以应用于小胶质细胞激活发挥重要作用的大脑退行性疾病，例如阿尔茨海默病和帕金森病。