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Functional Role of CADM1 during Type 1 Diabetes Pathogenesis

Type 1 diabetes (T1D) is characterized by the hyperglycemia resulting from the autoimmune destruction of the insulin-expressing β-cells of the pancreas. As the prevalence of the disease continues to increase worldwide, it remains imperative to identify therapeutic strategies that can (1) preserve pancreatic beta-cell mass and function and (2) prevent the immune response that initiates the pathogenesis of T1D. Cell adhesion molecule 1 (referred to as human CADM1 and mouse Cadm1, and also known as SynCAM1, TSLC1, Igsf4a, and Necl2) is an immunoglobulin-domain-containing membrane protein shown to mediate homo-and heterophilic cell-to-cell contact with other Cadm family members. We previously performed Cadm1 loss of function studies in β-cell lines and transgenic mice and established endogenous Cadm1 as a negative regulator of exocytosis and proliferation in pancreatic β-cells. It has also been shown that Cadm1+ cells will bind CD8+ T-cells via the receptor Class 1-restricted T-Cell-associated Molecule (Crtam) present in the immune cells; however to date, Cadm1-mediated cellular interactions have not been studied in the context of T1D. Here we hypothesize that CADM1 expression within the human pancreatic islet mediates cell-to-cell contact with infiltrating immune cells via the interaction of CADM1 present in alpha and beta cells with CRTAM on CD8+ T cells.The goal of this work is to perform immunohistochemical analysis to visualize CADM1isletexpression (in both alpha and beta cells) with markers of immune cell populations (i.e. CD8) within the islet infiltrate. This work seeks to: (1)identify CADM1 as a mediator of cell contact between specific immune cell populations and islet endocrine cells (both alpha and beta)and (2) validate the co-localization of CADM1 in the alpha and beta cell and CRTAM in CD8+ T-cells or NK immune cell populations. Completion of the proposed studies will determine whether CADM1 may be a potential therapeutic target for preserving beta cell mass and function and for attenuating the inflammatory response during the pathogenesis of T1D.

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