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

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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.