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Role of Nck adaptor proteins in kidney podocyte morphology

Dr. Nina Jones
University of Guelph
Biomedical Research Grants
2017 - 2019
Kidney biology
Chronic kidney disease (CKD) is a major public health issue that continues to rise coincident with the diabetes epidemic, and ~15% of Canada’s population is already living with this devastating illness. Very few treatments are available for advanced kidney disease, and these approaches are associated with considerable morbidity, mortality and health care costs, prompting a demand for new and more effective treatment strategies.
Fundamental discoveries over the past decade have highlighted the key role of the podocyte 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 a series of 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 podocyte foot processes and collapse of the actin cytoskeleton, resulting in slit diaphragm loss and proteinuria.

Our laboratory provided some of the first evidence that signaling from the slit diaphragm 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 mutant mouse models and complementary cell lines to explore the role of Nck in focal adhesion remodeling.
Emerging studies are highlighting the molecular heterogeneity of glomerular diseases; thus, our long-term objective is to translate this knowledge into rational design of more targeted therapies for the podocyte.

Dr. Nina Jones is an Associate Professor and Canada Research Chair in Eukaryotic Cellular Signalling at the University of Guelph, Ontario. She completed Ph.D. studies at the University of Toronto and obtained postdoctoral training at the Lunenfeld Tanenbaum Research Institute with the late Dr. Tony Pawson before her recruitment to Guelph in 2006. Her research investigates fundamental mechanisms of cell communication, and she has made significant contributions in understanding how such signalling pathways become deregulated in prevalent human pathologies such as kidney disease, cardiovascular disease and cancer. Dr. Jones has received numerous awards throughout her career, including a KRESCENT New Investigator Award, an Ontario Early Researcher Award, an NSERC-University Faculty Award, and a KFOC Merit Award for Outstanding Community Partner, and she is a member of the Royal Society of Canada College of New Scholars, Artists and Scientists. Research in Dr. Jones’s lab is presently supported by KFOC, CIHR and NSERC.