Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal Dominant Polycystic Kidney Disease
Abstract
Autosomal dominant polycystic kidney disease is a common inherited disorder. Patients are born with normal kidneys but, over the course of decades, they develop large fluid filled cysts that damage the normal kidney tissue. The damage caused by these cysts can lead ultimately to kidney failure, necessitating kidney transplantation or dialysis. There are currently no approved medications for this condition. In addition, there are few useful markers that permit disease severity to be assessed and the success of new therapies to be determined. Recent research reveals that the cells that line these cysts exhibit substantial abnormalities in the pathways through which they generate metabolic energy. Furthermore, correcting these abnormalities appears to slow cyst growth. We have found that the proteins that are encoded by the genes associated with autosomal dominant polycystic kidney disease regulate energy metabolism by helping cells to sense the presence of oxygen. Furthermore, we have identified drugs that can bypass this oxygen sensing activity and thus at least partially correct the energy metabolism defects in polycystic kidney disease cells. These drugs have been used previously in humans for other applications and they are well tolerated. Measurement of the byproducts of the perturbed metabolism in autosomal dominant polycystic kidney disease may reveal useful markers of disease progression and of the efficacy of new therapies. The present research project is aimed at examining whether the perturbed energy pathways constitute a promising new target for the development of novel therapies for autosomal dominant polycystic kidney disease. We will also determine whether metabolites produced as a result of the aberrant energy metabolism pathways in autosomal dominant polycystic kidney disease can serve as useful clinical markers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510420
Entities
People
- Kenneth Hallows
Organizations
- United States Army
- University of Southern California