The role of beta-catenin in cyst initiation in Autosomal Dominant Polycystic Kidn

Boston Children'S Hospital, Boston MA

Investigators

Abstract

DESCRIPTION (provided by applicant): Autosomal Dominant Polycystic kidney disease (ADPKD) is characterized by numerous cysts within the kidneys of afflicted individuals. The cysts formed in ADPKD can greatly enlarge the kidneys while replacing the normal kidney structures, resulting in reduced kidney function and progression to end-stage renal disease that can only be treated by lifelong dialysis or kidney transplants. As a disease that affects 1 in 800~1000 individuals, ADPKD is among the most common genetic disorders. In the United States, there are 600,000 individuals, and worldwide 12.5 million, with PKD [1]. Thus, ADPKD represents a major public health issue, and accounts for hundreds of millions (and perhaps over a billion) of dollars in health care costs, particularly for dialysis treatments and the cost of drgs that prevent transplant rejections, as well as the cost involved of decreased productivity and impaired quality of life of individuals with ADPKD. For all these reasons, it is of great importanc to discover treatments that directly affect the molecular causes of ADPKD, and that will prevent the progression to end- stage renal disease and dialysis or transplantation. Over the past 5 years the Kreidberg laboratory has investigated the role of receptor tyrosine kinase and Wnt signaling in the pathogenesis of ADPKD. Dr. Kreidberg's laboratory has found that Wnt signaling and beta-catenin expression is highly elevated in cyst lining cells in ADPKD. In this grant they propose to extend their studies to understand how b-catenin integrates signals from many pathways to cause the initiation of cyst formation in individuals with ADPKD. By understanding the processes involved in the initiation of cysts, we may identify therapeutic targets that inhibit the initiation or early progression of cysts, before they are clinically detectable.