Grant: Project Grant

Chronic kidney disease (CKD) is a major public health issue that continues to rise, and >3 million Canadians are already living with this devastating illness. Very few treatments are available for advanced CKD, and these approaches are associated with considerable 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 podocytes in the pathogenesis and progression of CKD. The ability of podocytes to remain anchored to the basement membrane and maintain filtration despite fluctuating hemodynamic forces is closely tied to their unique morphology. Podocytes extend interdigitating actin-rich foot processes that respond to their environment and alter their shape via a specialized cell junction known as the slit diaphragm. One of the earliest features of kidney disease is remodeling of foot processes and collapse of the actin cytoskeleton, and though this is reversible, prolonged dysfunction culminates in podocyte detachment. Our lab provided some of the first evidence that slit diaphragm signaling directly regulates actin dynamics and foot process morphology, and we have since validated the importance of such signaling in podocyte injury and repair. Our studies are now revealing that significant crosstalk exists between the slit diaphragm and focal adhesions, which attach the podocyte to the basement membrane. We have identified the adaptor protein Nck as a molecular hub linking these signaling centres, and the studies proposed here will use biochemical, cellular and animal-based approaches to explore the role of novel Nck-associated signaling partners in cell adhesion dynamics. Emerging studies are highlighting the molecular heterogeneity of glomerular diseases, thus our long-term objective is to translate this knowledge into design of more targeted therapies.