Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of numerous cysts in affected kidneys that lead to renalfailure in about half of ADPKD patients. The disease burden from ADPKD in U.S. alone is estimated at 600,000 individuals and worldwide it exceeds 12 million. The costs of renal replacement therapy in ADPKD patients in the US exceeds $2 billion annually. The past 15 years have seen substantial progress in our understanding of the pathogenesis of PKD with notable discoveries including the identification of the causative genes, the recognition that somatic second step mutations initiate cyst growth and the discovery that the cilia/basal body complex is the focal point of the pathogenesis of renal cystic diseases in general, and of ADPKD specifically. Despite these major advances, there remain substantial gaps in our knowledge of the molecular pathogenesis of the disease, particular when it comes to the immediate signals downstream of the PC1/PC2 receptor channel complex. These gaps undermine our ability to achieve a comprehensive understanding of ADPKD and directly limit our ability to rationally and effectively target ADPKD for therapy. A critical step for promoting deeper scientific understanding of the factors underlying polycystic kidney diseases and for promoting interest in efforts to develop therapies, is to achieve a compelling and precise definition of the target pathway(s) in ADPKD. The impediments to achieving a comprehensive understanding of ADPKD are two-fold. First, PKD is a disease affecting the development and, more importantly, the maintenance of three dimensional solid organ structure in the kidney and liver. As such, surrogate ex vivo systems based in two or three dimensional cell culture are inadequate for discovery of pathways central to PKD. The relevant readout for the cystic phenotype in such systems, if it exists, is not known. Second, there has been no strategy that has been successful for unknown pathway discovery downstream of the PKD genes. Rather, pathway discovery has been based on examining known pathways, such as those associated with proliferation and planar polarity, as candidates for dysregulation in PKD. We hypothesize that the polycystins act in an as yet undiscovered novel pathway(s) that is most clearly functional in intact organs and the discovery of which requires unbiased, phenotypically-driven forward genetic approaches in whole mammalian organisms. The current proposal puts forth a powerful and novel set of studies to achieve this goal. We propose to use transposon mediated somatic insertional mutagenesis based on a uniquely modified PiggyBac (PB) transposon system to discover activating mutations on a wild type background that result in cyst formation in the mouse kidney. We will do the same for loss-of-function mutations using a background sensitized to cyst formation by mutations in the ADPLD gene, Sec63. Since PB transposition may also yield micro-tumors in the kidney, we will use this system to uncover oncogenic pathways in the kidney as well. Finally, we will use this system to define the therapeutic expectations resulting from selective reactivation of the polycystin pathways in cyst cells. PUBLIC HEALTH RELEVANCE: Autosomal dominant polycystic kidney disease (ADPKD) affects 600,000 individuals in the US adds over $2 billion to health care costs annually. Improved understanding of the molecular basis for this disease is the best means of moving toward treatment. This proposal will use a novel state-of-the-art genetic analysis in mouse kidneys to discover mechanisms underlying ADPKD that have not been previously known and which will improve the prospects for finding effective treatments for the disease.
NIH ExPorter
NIH ExPorter