Pathogenesis and treatment of multiple sclerosis-COMBINED ABSTRACT- This Program Project is to understand regulatory underlying inflammation in the central nervous system (CNS) as it relates to the human demyelinating disease, multiple sclerosis (MS). The approach seeks to abrogate CNS inflammation therapeutically and to up- regulate repair pathways pertinent to CNS remyelination While the etiology and pathogenesis of MS remain unknown, compelling evidence exists for immune-mediation in the demyelinated MS plaque and from a number of investigators on animal models, it has been shown that blocking of inflammation in the CNS frequently leads to remyelination. The Program combines the efforts of three independent investigators with different but complimentary skills who have worked together on MS for several years and who propose projects that target different hypotheses on factors regulating CNS inflammation. The first project (Raine) will examine autoimmune demyelination in a mouse lacking the chemokine receptor, CCR2, a molecule necessary in monocyte trafficking to sites of inflammation; the expression of a novel growth factor, glial growth factor 2, a known potentiator of remyelination, and its receptor, within the CNS of animals with demyelinating disease and in MS lesions; and progenitor oligodendrocytes in MS lesions of different ages The next project (Brosnan) targets mutations in chemokine receptors, their role and effects upon CNS inflammatory pathways and their presence in MS, and molecules related to the NF kappaB signaling cascade during inflammation and in MS lesions. The final project (Berman) will apply an in vitro model of the human blood-brain barrier (BBB) to the roles of chemokines and chemokine receptors in leukocyte migration into the CNS; the effect of the regulatory cytokine, IFNbeta, a cytokine used to treat MS, upon molecular expression (cytokine, chemokine and adhesion molecule), and alterations in the molecular profile of a number of pro- inflammatory mediators during leukocyte transmigration. Each of the projects will incorporate examination of MS material and their combination under one Program will be mutually reinforcing. Since a major driving concept in this proposal is that down-regulation of pro- inflammatory pathways is a factor sine qua non for the up-regulation of myelin repair genes and CNS remyelination in MS, this proposal may be of considerable therapeutic import for the MS patient.
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