? ? Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common potentially lethal genetic diseases. It occurs worldwide and affects about 1 in 500 to 1000 Americans. The costs for treatment of end-stage renal disease are estimated to exceed 1.5 billion US dollars per year, not including the costs for treatment of other renal and extrarenal manifestations. Over the last 20 years this Program Project Grant (PPG) has contributed significantly to our understanding of the natural history of this disease. The long-term objective for the competitive renewal is to develop strategies to prevent disease progression in patients with ADPKD. Combining a clinical trial with investigations into genetic mechanisms of disease severity and basic research in animal models and cell culture systems will advance the understanding of ADPKD on several fronts. This competitive renewal continues to take advantage of the unique adult and child population which has been assembled over the past 20 years of the PPG. This patient population will be used in Project 4 - Effect of Statin Therapy on Disease Progression in Children with ADPKD - and in Project 1 - Genetic Studies of ADPKD. The premise of Project 1 is that identifying specific PKD mutations as well as modifying genes that promote disease severity will not only enhance the understanding of ADPKD pathophysiology, but will also allow selection of high-risk patients for treatment trials. Projects 2 and 3 will complement the two clinical investigations by performing basic science studies which have clinical implications for patients with ADPKD. Project 2 investigates the role of mTOR (mammalian target of rapamycin) signaling in the renal disease of PKD animal models. Our previous studies have shown that rapamycin markedly decreases PKD in the Han:SPRD rat, suggesting that rapamycin may be an effective treatment for patients with ADPKD. Project 3 examines the pathogenesis of hepatic cystic disease. As ADPKD patients live longer, the morbidity relating to massive liver cysts increases, yet very little is known about the pathogenesis of liver cysts. This multi-pronged approach to determine the response to statin therapy in ADPKD subjects, to decypher the genetic determinants of specific clinical manifestations in ADPKD, to evaluate the potential mechanisms of rapamycin as a treatment for ADPKD, and to understand the process of liver cyst formation will further the ultimate goal of preventing disease progression in ADPKD. ? ? ?
