Cytokines in Glial Cells and EAE Brain

描述（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，其中炎症介质诱导的促炎症事件（由活化的浸润单核细胞和内源性神经胶质细胞即星形胶质细胞和小胶质细胞分泌）决定病理生物学中炎症反应的结果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（EAE）中的抗炎特性，由于观察到他汀类药物的抗炎特性，这些药物现在正在许多神经炎性疾病中进行测试，包括MS，中风和阿尔茨海默病。然而，关于它们在炎性疾病过程中的作用机制知之甚少。作为酶HMG-CoA还原酶的抑制剂的他汀类药物通过减少二级蛋白质修饰所需的类异戊二烯和膜合成所需的胆固醇的合成来调节甲羟戊酸途径，特别是富含受体的细胞膜结构域，称为“脂筏”，以及分别为线粒体电子传递链和糖蛋白的N-糖基化所需的泛醌和多萜醇。拟定研究旨在鉴定负责洛伐他汀抗炎活性的甲羟戊酸途径代谢产物及其对“脂筏”结构和功能的影响。这些富含受体的脂筏结构域富含胆固醇、鞘磷脂和神经酰胺以及异戊二烯化GTP酶，用于传递促炎性丝氨酸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GT3通过这些脂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MS患者提供有效治疗的可能性。我们非常兴奋的是，我们实验室发起的这些基础研究可能成为MS和其他炎症性疾病治疗的基础。

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.