PATHOPHYSIOLOGY OF RECESSIVE POLYCYSTIC KIDNEY DISEASE

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OVERALL DESCRIPTION (Taken directly from the application) The overall objective for the development of an Interdisciplinary Center for Polycystic Kidney Disease Research at Case Western Reserve University (CWRU) is to attract a partnership of interdisciplinary research among investigators who will use complementary and integrated approaches to study the molecular and cellular pathophysiology of autosomal recessive polycystic kidney disease (ARPKD). ARPKD has an incidence of 1: 10,000 to 1: 40,000, has a mortality of 40-65% in the newborn period, and accounts for approximately 5% of all end-stage renal disease in children. Other than end-stage renal disease therapy and palliative measures designed to treat the complications of progressive portal hypertension, there is no known therapy for progressive renal cyst formation and enlargement or progressive biliary ectasia and fibrosis in ARPKD. Therefore the overall goal of the Center is to support scientific investigation directed at delineating the fundamental aspects of the disease process which will translate into the design of preventative and/or curative strategies for ARPKD. An ancillary objective of the Center is to attract new scientific expertise to the study of polycystic kidney disease. To achieve the stated objectives of the Center, the program involves a interdisciplinary research team drawn from the Departments of Pediatrics, Genetics, and Physiology & Biophysics at CWRU. The three Projects, three Cores, and two Pilot and Feasibility studies are scientifically integrated into an overall scheme which follows directly from current understanding of the molecular and cellular pathophysiology of ARPKD. Project 1, "Epithelial Growth Factor Mislocalization in ARPKD" focuses on a key process mediating abnormal epithelial cell proliferation. Project 2, "Altered Collecting Tubule Ion Transport in ARPKD" focuses on abnormalities in key ion transport processes which mediate altered tubular fluid secretion. Project 3, "Pharmacological and Genetic Therapy of ARPKD" is a translational project to develop therapeutic strategies which target key processes operative in the development and progression of disease. To support the scientific program, an Administrative Core will coordinate Center activities and specifically focus on maximizing scientific interactions of Center Investigators while monitoring and critically evaluating scientific process and encouraging new research in polycystic kidney disease-related areas. A Transgenic & Animal Resource Core will facilitate whole animal experimental approaches for all projects of the Center using state-of-the-art molecular genetic technology. A Cell Culture Core will provide and maintain primary cells and cell lines from human and murine control and cystic kidneys for the proposed studies. Though largely focused on the molecular and cellular pathophysiology of ARPKD, much of the basic knowledge and many of the treatment strategies developed by the Center will also have relevance to the study and treatment of autosomal dominant polycystic kidney disease.