Role of B7-1 in Podocytes in Pathogenesis of Proteinuria

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DESCRIPTION (provided by applicant): B7-1 (CD80) is a transmembrane protein of B cells and other antigen presenting cells, which was originally identified as a regulator of T cell activation and tolerance through CD28 or CTLA-4 binding on T cells. We previously reported that under pathological conditions with FP effacement and proteinuria, kidney podocyte express B7-1. The clinical significance of these results was underscored by the observation that podocyte B7-1 expression correlates with the severity of human lupus nephritis Here we propose to test our central hypothesis that B7-1 in podocytes contributes to the pathogenesis of proteinuria by altering podocyte actin dynamics, podocyte adhesion to the GBM, and slit diaphragm structure and function. To test this hypothesis we propose the following three Specific Aims. The first Aim will define the molecular mechanism whereby B7-1 orchestrates the reorganization of the podocyte actin cytoskeleton. Specific Aim two seeks to explore the role of B7-1 in podocyte adhesion to extracellular matrix. The third Aim will determine the contribution of podocyte B7-1 expression to the pathogenesis and progression of proteinuric kidney diseases. If our hypothesis is correct, the work proposed here will have broad significance in the long-term, because it will establish insight into the dynamics of the interaction between B7-1, the podocyte actin cytoskeleton and the SD complex in proteinuric kidney diseases. This should in the long-term enable us to develop novel, selective podocyte-protective therapies that tackle proteinuria and glomerulosclerosis by blocking the activity of B7-1 in podocytes. PUBLIC HEALTH RELEVANCE: The work proposed here should provide insight into the molecular mechanism whereby B7-1 expression in podocytes causes proteinuria. This should in the long-term enable us to develop novel, selective podocyte-protective therapies that tackle proteinuria and progression of glomerulosclerosis by blocking the activity of B7-1 in podocytes.