Effect of Reexpression of Endogenous Polycystin-1 in Polycystic Kidney Disease
Abstract
This project addresses the Fiscal Year 2014 Peer Reviewed Medical Research Programs Congressionally Directed Topic Area of polycystic kidney disease (PKD). The majority of cases of autosomal dominant PKD are caused by mutations in PKD1, a gene that encodes the protein polycystin-1 (PC1). While it is clear that loss of PC1 function leads to PKD, it is not known whether ongoing PC1 deficiency is necessary for cyst progression or whether progression occurs due to secondary responses not directly dependent on the ongoing absence of PC1. This is a critical question that must be addressed, as its answer is relevant to the development of effective therapies. The objective of this project is to determine the consequences of re-expression of PC1 in cystic mice. The hypothesis is that PC1 deficiency is essential for ongoing cyst growth and that re-expression of PC1 in cystic cells will restore a normal cellular phenotype, halting or even reversing cyst progression. To meet the objective and address this hypothesis, a mouse in which functional PC1 protein expression can be induced following a period of cystic disease progression has been engineered. This is the first and at present the only system in which re-expression of the endogenous Pkd1 gene and PC1 protein can be achieved at any point prior to or after the initiation of cystic disease. Results obtained from these studies will be immediately applicable to the development of patient care. If re-expression of PC1 halts or reverse PKD then therapies designed to restore or mimic PC1 function should be aggressively pursued. In contrast, if re-expression of PC1 does not halt or reverse PKD, then therapies that mitigate secondary factors that drive PKD progression should be pursued. In addition, these studies will have an immediate impact on PKD research by determining if an optimal developmental period for restoration of PC1 function exists, and by identifying potential secondary factors that promote disease progression independent of the absence of PC1.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610077
Entities
People
- Stephen Parnell
Organizations
- United States Army
- University of Kansas Medical Center