Invasion of leukocytes into the pancreatic islets and the selective destruction of the insulin-secreting beta cell characterize the autoimmune disorder insulin-dependent diabetes mellitus (IDDM). The objective of this proposal is to investigate the role of the adhesion molecule CD44 in the mechanism by which lymphocyte invasion of the islet is initiated resulting in the eventual destruction of the beta cell. CD44 is a surface glycoprotein with homology to cartilage link protein, that is heavily modified post-transcriptionally, with the capability to incorporate glycoaminoglycans. The CD44 molecule presents variations in the primary structure known as isoforms, generated by a RNA alternative splicing mechanism. Based on preliminary results obtained in the non-obese diabetic mice (NOD), we hypothesize that a specific subset of CD44 isoforms may be involved in delivering key signals for lymphocyte recruitment into the islets. We propose first to extend our preliminary data by determining which combinations of CD44 isoforms are expressed by islets cells at different stages of insulitis. Second to explore the pattern of expression of CD44 variants in islet infiltrating lymphocytes at different stages of insulitis. Finally we want to search for potential ligands of the predominant subsets of CD44 variants expressed by infiltrating leukocytes. We hope that the studies that comprise this proposal will help to elucidate the molecular determinants responsible for insulitis and beta cell directed autoimmunity.
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