Grant: Operating Grant

Scarring is a major cause of chronic organ failure, accounting for up to 50% of all deaths in the developed world. In the kidney, scarring is the final common pathway of damage activated by nearly all forms of chronic kidney disease. If left unchecked, kidney scarring can lead to kidney failure, an increasingly common, costly, and life-threatening condition requiring dialysis or kidney transplantation for survival. Unfortunately, no safe and effective anti-scarring treatments exist. Transforming growth factor-beta (TGF-beta) is the main stimulus for scar production. Drugs that block TGF-beta are not widely used as anti-scarring agents because TGF-beta not only promotes scarring, but also controls many other important non-scarring functions in the body. Following injury and especially with scarring, organs become stiffer. Recent studies have demonstrated that fibroblasts, the main source of scar tissue in the kidney, can sense this increased stiffness, and react by augmenting their responsiveness to TGF-beta. We have identified two proteins named TAZ and YAP which play a critical role in regulating stiffness-dependent fibroblast scarring responses. TAZ and YAP are activated when fibroblasts are grown on a stiff surface reminiscent of an injured, fibrotic kidney, and inactivated when fibroblasts are grown on a soft, healthy kidney-like surface. We have shown that active TAZ and YAP may promote fibroblast scarring responses to TGF-beta, and that inactivation of these proteins seems to block these scarring responses. The proposed studies will explore how TAZ and YAP are activated by kidney stiffening, how they promote TGF-beta-induced fibroblast scarring responses, and using specialized gene-modification strategies will test whether loss of TAZ and/or YAP can prevent kidney scarring in animal models of chronic kidney injury. Ultimately these studies aim to identify new safe and specific anti-scarring agents for the treatment of patients with chronic kidney disease.