Grant: Project Grant

Chronic kidney disease (CKD) is a major public health issue that continues to rise coincident with increased longevity and the obesity, diabetes and hypertension epidemic, and ~3 million Canadians are already living with this devastating illness. Presently, dialysis and transplantation are the only forms of treatment for advanced kidney disease, and these approaches are associated with considerable morbidity, mortality and healthcare costs. Despite the burden of disease, the molecular and cellular basis of CKD is poorly understood, limiting opportunities for development of new therapies. Fundamental discoveries over the past decade have highlighted the key role of the podocyte in the pathogenesis and progression of CKD. These cells are a crucial component of the glomerular blood filtration barrier, and their function is closely tied to their unique morphology. Podocytes extend a series of interdigitating actin-based foot processes that are bridged by specialized signaling junctions known as slit diaphragms (SD). One of the earliest features of kidney disease is remodeling of podocyte foot processes and collapse of the actin cytoskeleton, resulting in disrupted filtration and proteinuria. Our lab provided some of the first evidence that signaling from the SD directly regulates foot process morphology, and we have since validated the importance of such signaling in podocyte injury and repair. These discoveries provide a molecular foothold to help understand the basis of podocyte function, and the underlying hypothesis of our research program is that perturbations in SD signaling are the initiating cause of podocyte injury progressing to CKD. Leveraging a series of novel mutant mouse models and complementary cell-based tools, the goal of this proposal is to identify molecular and cellular processes that are coordinated by the central SD protein nephrin. Our long-term objective is to translate this knowledge to the bedside to identify new podocyte-specific therapies.