Nephrotic syndrome (NS) is an important cause of morbidity and mortality, particularly in children. Although the morphologic changes in the glomerulus associated with NS have been known for 35 years, we still do not have a proper understanding of what causes them in most cases. In particular Minimal Change NS and Congenital NS have similar glomerular pathology showing fusion of the delicate foot processes of the glomerular epithelial cell (podocyte), while in Membranous Nephropathy it is likely that in most cases antibodies are formed that react with an antigen on the foot processes so that clumps of immune deposit accumulate and interfere with the function and structure of the glomerular filtration barrier. To make progress in treating these conditions we need to understand in molecular terms how the structure of the glomerular filter is maintained. To achieve this goal we have looked for molecules which are restricted to the glomerulus with the hypothesis that it will be these molecules that are abnormal or acting as antigens for the above conditions. This application focuses on a newly discovered protein, GLEPP1, which appears from its nucleotide sequence to belong to a family of proteins called membrane protein tyrosine phosphatases (PTPs). PTPs are thought to act as receptors that transmit information from outside to inside the cell. Since GLEPP1 is unique to the podocyte (the only protein so far described with this characteristic) and it appears in the deveeloping glomerulus during foot process formation, and disappears in a model of foot process fusion, we believe that GLEPP1 might well play a role in regulating foot process structure and function. We are therefore requesting support to complete the cloning and sequencing of rabbit GLEPP1, to determine its protein structure, to confirm that it does indeed function as a phosphatase, to determine which proteins are substrates for GLEPP1 phosphatase action, and finally to evaluate GLEPP1 expression and structure in two models of foot process fusion in the rabbit and also in human glomerular diseases. We anticipate that a knowledge of how GLEPP1 works will provide important new insight into the regulation of foot process structure and function. In addition we hope that this information will lead to new and more effective ways of treating nephrotic syndrome in children.
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