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

项目总结 多发性硬化症(MS)治疗的最新进展导致了疗效的提高 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Natalizumab相关的白质脑病和与Fingolimod相关的心动过缓，这限制了他们的 用于那些被确认为这些不良反应的高风险的多发性硬化症患者。这些风险是 归因于每种药物相对独特的性质，因此有新的策略来阻碍中枢神经系统的免疫 细胞贩运可能导致开发治疗多发性硬化症的有效新药，其安全性特征截然不同 与目前批准的药物不同。亲环素A是一种蛋白质，当分泌时有助于吸引免疫 细胞转移到炎症部位。目前尚不清楚亲环素A是否与中枢神经系统炎症有关。 我实验室的数据显示，在一种名为实验性变态反应性脑脊髓炎的多发性硬化症动物模型中 (EAE)，用一种非选择性地阻断亲环素作用的药物治疗动物，可以降低 疾病和减少进入中枢神经系统的免疫细胞的数量。为了清楚地定义亲环素抑制 改善中枢神经系统炎症，我们提出了一项研究，以检验亲环素A对中枢神经系统有贡献的假设 通过帮助将免疫细胞招募到中枢神经系统而引起炎症。在研究的目标1中，我们建议界定 亲环素A基因缺失小鼠的EAE病程和生物学研究 亲环素A会损害免疫细胞在中枢神经系统的募集，并改变免疫反应的类型。在……里面 目的2，我们建议测试一种新的特异性抑制细胞外亲环素A的化合物，以测试 假设阻断细胞外(分泌型)亲环素A就足以改善EAE的病程。这个 这项提案的长期目标是确定亲环素如何在多发性硬化症患者中用于治疗目的。 这项建议的目的是确定亲环素A的缺失减少疾病的机制 进一步明确亲环素A在中枢神经系统炎症中的作用。这样的结果预计将 通过提供开发亲环素抑制剂所需的知识来产生重要的积极影响 治疗多发性硬化症等中枢神经系统炎症性疾病，从而完成NINDS的使命，寻求 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.