Genetic Determinants of Pathologic Heterogeneity in MS

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DESCRIPTION (provided by applicant): Our preliminary studies suggest there is intra-individual homogeneity within both early and chronic MS lesions with respect to pathologic measures of inflammation, dominant immune effector mechanisms of active demyelination, and extent of tissue injury and repair. Evidence of intra- individual pathological homogeneity may reflect genetic variation in loci controlling lesion formation. We propose to collect and pathologically phenotype a large sample of MS lesions in order to examine both the complex relationships between inflammation, demyelination, remyelination, and axonal injury in both early and chronic MS lesions, as well as investigate the relationship of demographic and clinical variables with these pathologic outcomes. In addition, we will assess the degree of intra-individual homogeneity for these well defined specific histo- and immunopathological outcomes in order to validate our preliminary observations of intra-individual homogeneity, and more accurately establish the number of cases within each of the respective pathological phenotypes available for future genetic study. We aim to establish a reliable and statistically robust MS Tissue-DNA Databank which will use pathology as a novel intermediate outcome for future genetic-association studies The proposed studies will yield a tremendous resource of patient material having both detailed and quantitative pathologic analyses and DNA, and will provide the framework for an efficient and cost-effective transition from discovery of chromosomal regions or candidate genes of interest in genome-wide linkage, population-association and tissue microarray studies, to detailed clinical-pathologic analysis in order to determine pathogenic relevance. By stratifying patients based on specific pathological features, we will increase the likelihood of identifying potential genetic contributions common to each category. Furthermore, there are pragmatic reasons for supporting additional research into MS pathology and genetics. A more fundamental understanding of the variable pathological and genetic factors involved in MS lesion evolution will not only provide additional pathogenetic insights into MS, but will lead to improved determination of long term prognoses, as well as impact the selection of current, and design of future, treatment approaches tailored to the patient.