Cytokines in Glial Cells and EAE Brain

描述（由申请人提供）：多发性硬化症（MS）是一种自身免疫性脱髓鞘疾病，在这种疾病中，炎症介质（由活化的浸润性单核细胞和内源性胶质细胞，即星形胶质细胞和小胶质细胞分泌）介导的促炎事件的诱导，决定了病理生物学中炎症反应的结果(髓磷脂的丢失，我们实验室的研究首次记录了他汀类药物在培养细胞和实验性自身免疫性脑脊髓炎（一种多发性硬化症动物模型）中的抗炎特性。由于观察到他汀类药物的抗炎特性，这些药物目前正在许多神经炎症性疾病中进行测试，包括多发性硬化症、中风和阿尔茨海默病。然而，关于它们在炎症性疾病过程中的作用机制知之甚少。他汀类药物作为HMG-CoA还原酶的抑制剂，通过减少二级蛋白修饰所需的类异戊二烯的合成，以及胆固醇的合成，尤其是富含受体的细胞膜结构域“脂筏”的合成，以及线粒体电子传递链和糖蛋白n -糖基化所需的泛醌和醇醇的合成，来调节甲羟戊酸途径。拟议的研究旨在确定甲羟戊酸途径的代谢物，这些代谢物负责碘伐他汀的抗炎活性及其对“脂筏”结构和功能的影响。这些富含受体的脂质筏结构域富含胆固醇、鞘磷脂、神经酰胺和异丙烯酰化gtpase，用于传递促炎细胞因子介导的信号传导过程。研究旨在了解他汀类药物对受体及其效应蛋白募集的作用机制，以及小GTPase通过这些脂质筏结构域诱导促炎信号的作用机制。因此，研究他汀类药物对EAE/MS疾病过程中炎症反应中脂质筏结构和功能的作用机制具有重要意义。深入了解这些药物的作用机制可能为多发性硬化症患者提供有效治疗的可能性。我们非常兴奋的是，我们实验室开展的这些基础研究可能会成为治疗多发性硬化症和其他炎症性疾病的基础。

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is an autoimmune, demyelinating disease in which the induction of proinflammatory events orchestrated by inflammatory mediators (secreted by activated infiltrating mononuclear cells and endogenous glial cells i.e. astrocytes and microglia) determines the outcome of the inflammatory reaction in the pathobiology (loss of myelin, oligodendrocytes and axons) of MS. Studies from our laboratory were the first to document the anti-inflammatory properties of statins in cells in culture and in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Because of the observed anti-inflammatory properties of statins, these drugs are now being tested in a number of neuroinflammatory disorders including MS, stroke and Alzheimer's disease. However, little is known regarding their mechanisms of action in the inflammatory disease process. Statins as inhibitors of the enzyme HMG-CoA reductase regulate the mevalonate pathway by decreasing the synthesis of isoprenoids required for secondary protein modifications, and cholesterol, required for the synthesis of membranes especially receptor rich cellular membrane domains known as "lipid rafts" and ubiquinone and dolichol required for mitochondrial electron transport chain and N-glycosylation of glycoproteins, respectively. The proposed studies are designed to identify the metabolite(s) of the mevalonate pathway responsible for the anti-inflammatory activity of Iovastatin and its effects on structure and function of "lipid rafts". These receptor rich lipid raft domains are rich in cholesterol, sphingomyelin and ceramide and isoprenylated GTPases for transmission of proinflammatory cytokine-mediated signaling processes. Studies are designed to understand the mechanism of action(s) of statins on recruitment of receptor and their effector proteins and that of small GTPase for induction of proinflammatory signals through these lipid raft domains. Therefore, it is of interest to study the mechanism of action of statins on lipid raft structure and function in inflammatory responses that are responsible for the EAE/MS disease processes of. In depth knowledge of the mechanisms of action of these drugs may offer the possibility of developing effective therapy for MS patients. We are very excited about the possibility that these basic studies initiated from our laboratory may become the basis of therapeutics for MS and other inflammatory diseases.