The mechanisms responsible for the Nephrotic Syndrome are largely unknown. Podocytes are the major cells responsible for maintaining the filtration barrier of the renal glomerulus. The glomerular filtrate passes between the delicate interdigitating podocyte foot processes and across the slit diaphragm (a modified intercellular junction) between them. In glomerular injury these foot processes become effaced in association with development of leakiness of the filter. They searched for molecules that might regulate podocyte foot process structure and function, to better understand the regulation of the glomerular filter and the abnormalities that occur in the Nephrotic Syndrome. GLEPP1 is a receptor-like membrane protein tyrosine phosphatase (PTPase) that is resident on the foot processes of the podocyte. GLEPP1 has been cloned, characterized and sequenced. A hypothesis is that the receptor regulates the glomerular filtration of protein, and that it does so through its ability to dephosphorylate proteins in foot processes, possibly those which control the slit diaphragm (special intercellular junction) between foot processes. To unequivocally establish the importance of this new mechanism they will knock out the GLEPP1 gene, and perform further experiments to document the mechanism by which GLEPP1 controls glomerular permeability. They will analyze how this receptor signals downstream to its effector molecules. They will determine whether loss of GLEPP1 is associated with poor prognosis for the glomerulus in FSGS, and will use a rat model to examine podocyte injury with the concept that GLEPP1 may be a useful marker for predicting response to therapy and prognosis. Together, these analyses will significantly advance our understanding of how the glomerular filter is regulated, and possibly provide new insights about how pathologic processes affecting the filter, such as the Nephrotic Syndrome, can be treated.
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