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，由炎症介质(由活化的浸润性单个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)诱导的促炎事件决定了多发性硬化症的病理生物学(髓鞘、少突胶质细胞和轴突的丢失)中炎症反应的结果。我们实验室的研究首次证明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，EAE是多发性硬化症的动物模型。由于观察到他汀类药物的抗炎特性，这些药物目前正在包括多发性硬化症在内的许多神经炎性疾病中进行测试。中风和阿尔茨海默病。然而，对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，通过减少二次蛋白质修饰所需的异戊二烯类化合物和胆固醇的合成来调节甲戊酸途径，其中胆固醇是膜合成所需的，特别是膜的富含受体的细胞膜结构域被称为脂筏，以及线粒体电子传输链和糖蛋白的N-糖基化分别所需的泛醌和二苯二酚。这些研究旨在确定甲伐他汀途径的代谢物(S)，该代谢物负责Iovastatin的抗炎活性及其对脂筏结构和功能的影响。这些富含受体的脂筏结构域富含胆固醇、鞘磷脂、神经酰胺和异戊二烯基化的GTP酶，用于传递促炎细胞因子介导的信号过程。研究旨在了解他汀类药物(S)对受体及其效应蛋白募集的作用机制，以及小GTP酶通过这些脂筏结构域诱导促炎信号的作用机制。因此，研究他汀类药物在炎症反应中对脂筏结构和功能的作用机制是有意义的，这些炎症反应是导致EAE/MS疾病过程的原因。深入了解这些药物的作用机制可能为开发治疗多发性硬化症的有效方法提供可能。由我们实验室发起的这些基础研究可能成为治疗多发性硬化症和其他炎症性疾病的基础，我们对此感到非常兴奋。

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.