The Role of c-Src in the Pathophysiology of ARPKD

Project Description Narrative:

The overall objective of the Avner-Sweeney lab is to unravel the basic molecular and cellular pathophysiology of polycystic kidney disease (PKD), and utilize such information to design specific therapies, which target the cystic cellular phenotype. Despite the identification of the major disease genes for autosomal recessive PKD (ARPKD) and autosomal dominant PKD (ADPKD), no specific therapies exist to limit renal cyst formation and progressive enlargement, nor the biliary plate abnormalities and hepatic fibrosis which lead to portal hypertension in ARPKD.

This project is specifically focused on delineating the role of c-Src in the abnormal cellular phenotype of cystic epithelium in the autosomal recessive form of PKD (ARPKD). In addition, it will test the possible therapeutic role of c-Src inhibitors in a rat genetic orthologue of ARPKD, the PCK rat.

The project has the potential to lead to specific improvements in health status, longevity and quality of life for children with ARPKD, who have significant renal and cardiovascular morbidity and mortality. These studies will be relevant to ADPKD (the most common human renal genetic disorder) in that similar EGFR c-Src interactional abnormalities have been described. A similar paradigm of EGFR over-expression and Src-mediated proliferation has been described in many cancers (including breast, colon, prostate, head and neck) making this study relevant to oncology. The current application will provide pilot data for future extramural R-level funding, as well as multidisciplinary collaboration.