Adult onset polycystic kidney disease, ADPKD, is a common dominant genetic disorder characterized by the progressive enlargement of multiple renal cysts leading to a decline in renal function and culminating in renal failure in 50% of patients. Mutations in two genes, PKD1 and PKD2, which encode polycystin 1 (PC-l) and polycystin 2 (PC-2) respectively are major determinants in adult onset polycystic kidney disease (1,31). Since the last submission of this grant, there has been an explosion of new information on the molecular biology of the polycystins. This new information has provided the exceptional opportunity to understand the role of the polycystins in renal function and in the pathophysiology of ADPKD. Experiments funded during the previous budget period showed that PC-1 and PC-2 form an ion channel complex in the plasma membrane and that transfection of additional PKDlin MDCK cells promotes tubule formation. In the current renewal application, a combination of molecular and physiological experiments will be used to address the following questions: What regulates ion channel currents generated by the co-assembly of PC-1 and 2? How do the polycystins influence ion channel trafficking during tubulogenesis? How does signaling within the polycystin complex alter ion channel processing? To develop new therapeutics for ADPKD, it is essential to understand how the polycystins function in tubulogenesis and to have experimental cell systems that will enable us to test the biological effect and potency of potential new therapies. Thus, new knowledge generated from studies within this proposal addressing questions pertaining to both tubulogenesis and new cell models will have direct benefit to human health.
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