We have previously identified a point mutation in thes Transient Receptor Potential Cation Channel 6 (TRPC6) gene causing an autosomal dominant form of familial focal and segmental glomerulosclerosis (FSGS). This P112Q substitution causes a marked alteration in TRPC6-mediated calcium signals in response to agonists such as angiotensin II. However, the precise mechanism by which the TRPC6P112Q mutation leads to the prototypical disease phenotype of FSGS is not clear. We hypothesize that the presence of a single TRPC6P112Q allele causes an intermediate phenotype which is sufficient to promote the development of renal disease and that the TRPC6P112Q protein may amplify injurious signals triggered by ligands such as angiotensin II that play a key role in promoting kidney injury and proteinuria. To test these hypotheses, we propose the following specific aims: (1) To define the intermediate phenotype conferred by heterozygosity for the TRPC6P112Q mutation in a unique resource of human cell lines from the FSGS2 family. These cell lines will be used to define the consequences of this mutation on calcium signaling, TRPC6 trafficking, cell growth and apoptosis. (2) To establish causality of the TRPC6P112Q mutation for FSGS using a mouse model. Extending the in vitro work in specific aim 1 to the in vivo setting, we will develop a knock-in mouse model of the heterozygous TRPC6P112Q mutation. (3) To determine whether expression of the TRPC6P112Q mutation only in podocytes is sufficient to cause proteinuria. TRPC6 is expressed in podocytes and abnormalities of podocyte function are essential to the pathogenesis of FSGS. We suggest that expression of the TRPC6P112Q protein in podocytes disrupts key cellular functions and we will test this by generating a transgenic mouse line expressing the mutant TRPC6P112Q protein only in podocytes. We anticipate that these animals will develop overt proteinuria and FSGS. (4) To define the consequences of TRPC6 deficiency in the kidney. We have hypothesized that the TRPC6P112Q mutation causes a gain-of-function phenotype of exaggerated calcium flux that generates glomerular injury. It is possible that the mutation alters some critical function of TRPC6 necessary for maintaining normal glomerular function. To distinguish these possibilities, kidney structure and function will be examined in a line of -/-TRPC6 mice. Our original hypothesis suggests that the absence of TRPC6 may confer resistance to kidney injury and proteinuria. We will test this in models of induced renal disease.
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