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 (ESRD) are estimated to exceed 1.5 billion US dollars per year, not including the cost for treatment of other renal and extrarenal manifestations. Over the last 15 years this Program Project Grant (PPG), which is the largest study of ADPKD manifestations in children and adults in the world, 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. This application focuses on ADPKD kidney and liver disease. Combining a clinical trial with investigations into genetic mechanisms of disease severity and with basic research in an animal model and cell culture systems will be the overall strategy to achieve the goal. The competitive renewal of the PPG continues to take advantage of the unique adult and child population, which has been assembled as a result of the 15-year PPG. This patient population will e used in the first Project-A randomized trial of anti-hypertensive therapy in children, adolescents and young adults with ADPKD- and in the second Project- Identification of modifying gene sin ADPKD. The premise is that identifying genes that promote disease severity will not only help to understand the pathophysiology, but will also allow development of new treatments and section of high-risk patients for treatment trials. The third and fourth will complement the two clinical investigations by performing basic science studies, which have clinical implications for patients with ADPKD. The third Project investigates the role of apoptosis and caspase (apoptosis) inhibitors in the progression to ESRD in the Han:SPRD rat model of ADPKD and in the Pkd2/WS25 mouse model provided by Dr. Somlo, and the fourth Project examines the pathogenesis of hepatic cystic disease. Very little is known about the pathogenesis of liver cysts and thus focused interventions are not possible. Study of the liver will also contribute to our understanding of the factors that cause ESRD in ADPKD.
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