Research Awards Recipients

Lay Abstract

BACKGROUND: Chronic kidney disease is an increasingly serious public health threat. About 12% of Canadians suffer from this condition. Significantly, the number of patients with kidney disease is increasing, because it is a consequence of very common ailments such as diabetes and hypertension, which lead to recurring damage to the kidney tissues. Injury initiates a cellular repair program to restore normal tissues, but ongoing tissue damage can overwhelm repair. As damage lingers, repair attempts do not turn off, and dysfunctional tissues get replaced by non-functional permanent scars. This diminishes kidney functions, and eventually causes kidney failure. Such a self augmenting scarring process is referred to as kidney fibrosis. Unfortunately, we cannot stop and/or reverse fibrosis, and in fact, we still do not fully understand how it develops and progresses. Intense research has focused on cellular and molecular events that activate repair and then turn it into a harmful scar-forming processes. However, little is known about mechanisms that suppress scar formation in healthy tissue, and turn the repair process off once tissues are healed. These fibrosis limiting mechanisms are understudied despite the potential that we could harness them to reduce scarring. This proposal will explore a potential suppressor of scar formation.
PREVIOUS WORK AND PURPOSE: My overall research aim is to obtain a better understanding of the cellular events that cause failed repair and scarring in the kidney, to allow the development of new interventions. In this proposal I wish to explore a new mechanism that may suppress the healing program in healthy tissues and could limit scarring after the injury is repaired. In our previous studies we used cultured kidney cells and mouse kidney disease models to discover new molecular pathways activated during healing, and overactivated in the process leading to fibrosis. We identified a molecular pathway that acts as a central sensor hub connecting harmful stimuli with healing or scarring. One of the key components of this molecular pathway is called GEF-H1. This molecule is key for normal kidney repair processes, but its overactivation can be harmful. We found that this protein is overproduced in a kidney fibrosis mouse model. Although the balance on-off regulation of GEF-H1 appears to be key for normal healing, the mechanisms that limit GEF-H1 activity and induce its deactivation once it is no longer needed, remain not well known. Looking for molecules that control GEF-H1, we identified a new candidate, a molecule named PP6, that can bind to GEF-H1 and suppress its activity. PP6 has various roles in cancer, but its possible involvement in kidney disease has not been studied. Interestingly, we also found that in a mouse kidney disease model PP6 abundance is reduced in the kidney, which could enhance the development of fibrosis. Our yet unpublished data revealed that when PP6 expression is reduced in kidney cells, a series of molecular events ensue that support processes leading to fibrosis. Our new findings support the idea that PP6 may be an essential stop signal, that can turn off the process of fibrosis in healthy tissues or following tissue repair. Thus, the objective of this proposal is to learn how PP6 controls various molecular events that are associated with fibrosis and establish this molecule as a potential suppressor of kidney scarring.
PRPOSED STUDIES: Using biochemical, cell biological and microscopic techniques in cultured kidney cells we will define how PP6 is inhibited by fibrosis conditions, and interfere with PP6 to test how this affects cellular functions connected to fibrosis. Next, we will develop and use a mouse model in which PP6 will be eliminated from the kidneys. In these mice we will study the development of experimental kidney fibrosis to reveal if PP6 indeed acts as a fibrosis reducer. In collaborative studies, we will investigate whether biopsies from kidney disease patients have alteration in PP6 abundance, to verify if this molecule has a role in human disease.
SIGNIFICANCE: This project will define a new molecular suppressor of fibrosis, that may be harnessed as a promising was to stop kidney scarring. Ultimately new drugs for the treatment of kidney fibrosis are essential to benefit millions of patients who suffer from chronic kidney disease.