Kidney fibrosis is a critical health problem in the United States because it represents the final common pathway of all chronic kidney diseases yet there is no approved drug to treat it. There is general agreement that myofibroblasts are the cell type responsible for scar formation in fibrotic kidney disease but little consensus about where these cells come from, which is a critical knowledge gap that needs to be brifged in order to discover new therapies to treat chronic kidney disease. We have discovered a new subpopulation of stromal cells, unappreciated in kidney science to date, that represents the major myofibroblast precursor population. These cells expand in fibrosis according to our genetic fate mapping experiments, and ablating these cells ameliorates fibrosis - proving their functional importance. In this proposal we aim to understand the role of these cells in health and chronic disease, to determine whether their ablation improves renal functional parameters in chronic kidney disease models, and to understand their functional capacities. We will use state of the art genetic approaches in vivo and complementary cell isolation, transplantation and in vitro studies to assess their properties ex vivo. Together, the proposed experiments represent a rigorous evaluation of our hypothesis that these cells play a critical role in kidney fibrogenesis and should be targeted therapeutically to halt chronic kidney disease.
Kidney fibrosis is the leading cause of kidney failure worldwide, and it represents an enormous health burden and unmet medical need. We have discovered a novel stromal cell type present in kidney that plays a critical role in the development of kidney fibrosis. We hypothesize that targeting these cells therapeutically will lead to new and effective treatments for humans with chronic kidney disease. The experiments in this application are designed to better define the origin and function of these cells in kidney disease, and to establish a proof of principle that targeting these cells will ameliorate kidney fibrosis.
