The contribution of cyclophilin A to immune-mediated inflammatory disorders of the central nervous system

项目摘要 最近在多发性硬化症（MS）治疗方面的一项进展导致了疗效的改善， 开发有效阻止免疫细胞进入中枢神经系统（CNS）的药物。 然而，这些药物存在严重的风险，例如进行性多灶性 与那他珠单抗相关的白质脑病和与芬戈莫德相关的心动过缓，这限制了他们的治疗。 用于确定为这些不良反应高风险的MS患者。这些风险 这归因于每种药物相对独特的性质，因此是阻碍CNS免疫的新策略。 细胞运输可能导致开发有效的MS新药， 与目前批准的药物相比。亲环素A是一种蛋白质，当分泌时，有助于吸引免疫细胞， 细胞转移到炎症部位。亲环素A是否特异性参与CNS炎症尚不清楚。 来自我实验室的数据显示，在称为实验性过敏性脑脊髓炎的MS动物模型中， (EAE)用非选择性阻断亲环素作用的药物治疗动物， 疾病和减少进入中枢神经系统的免疫细胞的数量。为了明确亲环素抑制 改善中枢神经系统炎症，我们提出了一项研究，以测试假设，亲环素A有助于中枢神经系统 通过帮助募集免疫细胞进入中枢神经系统来治疗炎症。在研究的目标1中，我们建议定义 EAE在遗传上缺乏亲环素A的小鼠中的过程和生物学，以检验EAE的缺失 亲环素A将损害免疫细胞向CNS的募集并改变免疫应答的类型。在 目的2，我们提出测试一种特异性抑制细胞外亲环素A的新化合物，以测试其对细胞外亲环素A的抑制作用。 假设阻断细胞外（分泌的）亲环素A足以改善EAE的进程。的 该建议的长期目标是确定如何将亲环素靶向用于MS的治疗目的。 该建议的目的是确定亲环素A的缺失减少疾病的机制 EAE中的负担，并进一步确定亲环素A在CNS炎症中的作用。这些结果预计将 通过提供开发亲环蛋白抑制剂所需的知识， 治疗CNS炎症性疾病，如MS，从而实现NINDS的使命， 关于神经系统的基本知识，并利用这些知识来减轻 神经系统疾病

PROJECT SUMMARY A recent advance in multiple sclerosis (MS) treatment that has led to improved efficacy has been the development of drugs that effectively block immune cells from entering the central nervous system (CNS). There are serious risks associated with these drugs, however, such as progressive multifocal leukoencephalopathy associated with natalizumab and bradycardia associated with fingolimod, which limit their use in individuals with MS who are identified as being high-risk for these adverse effects. These risks are attributable to relatively unique properties of each drug and therefore new strategies to impede CNS immune cell trafficking may lead to the development of effective new drugs for MS with safety profiles that are distinct from those of currently approved drugs. Cyclophilin A is a protein that when secreted aids in attracting immune cells to sites of inflammation. It is not known whether cyclophilin A is specifically involved in CNS inflammation. Data from my laboratory showed that in an animal model of MS termed experimental allergic encephalomyelitis (EAE), treating animals with a drug that non-selectively blocks the action of cyclophilins reduces the severity of illness and reduces the number of immune cells that enter the CNS. To clearly define how cyclophilin inhibition improves CNS inflammation, we propose a study to test the hypothesis that cyclophilin A contributes to CNS inflammation by helping to recruit immune cells into the CNS. In Aim 1 of the study, we propose to define the course and biology of EAE in mice that genetically lack cyclophilin A to test the hypothesis that the loss of cyclophilin A will impair recruitment of immune cells into the CNS and alter the type of immune response. In Aim 2, we propose to test a novel compound that specifically inhibits extracellular cyclophilin A to test the hypothesis that blocking extracellular (secreted) cyclophilin A is sufficient to improve the course of EAE. The long-term goal of this proposal is to define how cyclophilins can be targeted for therapeutic purpose in MS. The objective of this proposal is to define the mechanism by which the loss of cyclophilin A reduces the disease burden in EAE and further define the role of cyclophilin A in CNS inflammation. Such results are expected to have an important positive impact by providing the knowledge needed to develop cyclophilin inhibitors as therapies for CNS inflammatory disorders such as MS, and thereby fulfill the NINDS mission to seek fundamental knowledge about the nervous system and to use that knowledge to reduce the burden of neurological disease.