Research Interests

Although my work is currently focused on miRNAs in the kidney, I remain interested in other aspects of glomerular and podocyte biology. In particular:

Heparan sulfate proteoglycans (HSPGs) and glomerular function

As a postdoctoral fellow in the lab of Dr. Jeffrey Miner at Washington University in St. Louis I studied the role of the HSPG agrin in glomerular function. Anionic HSPGs in the glomerular basement membrane (GBM) are thought to confer glomerular charge-selectivity. Disruption of the charge barrier has long been touted as an underlying cause of proteinuria. As the predominant GBM-HSPG, agrin was considered a major determinant of charge-selective filtration and was thought to serve critical structural and signaling roles in the glomerulus.

To define roles for agrin in glomerular structure and function we studied agrin mutant mice. GBM charge was severely disrupted in agrin-deficient and podocyte-specific knockout mice, yet the filtration barrier remained structurally and functionally intact. Our work challenges the notion that agrin, and GBM charge in general, contributes to glomerular permselectivity.

Alport syndrome, type IV collagen and gene therapy

My doctoral research focused the role of type IV collagen in the pathogenesis of X-linked Alport syndrome (XLAS). This work was carried out under the supervision of Dr. Paul Thorner at the Hospital for Sick Children in Toronto. XLAS is a disorder characterized by nephropathy. ocular abnormalities and deafness that is caused by mutations in the COL4A5 gene encoding the a5 chain of type IV collagen.

We documented the spatiotemporal distribution of type IV collagen isoforms in the kidney and inner ear in a model of XLAS and correlated these to normal and pathologic changes in BM ultrastructure and function. Using an adenoviral vector encoding the a5 collagen chain we provided 'proof of principle' of the feasibility of gene therapy for XLAS.

GBM-agrin

GBM-collagen

podocytes