The glomerular basement membrane (GBM) forms a critical component of glomeruli, and is comprised of numerous proteins, many of whose individual functions are unknown. Much of the GBM is located between podocytes and endothelia, however, it also interacts directly with mesangial cells, a pericyte-like, contractile, support cell. Very little is known about the individual GBM proteins involved in this interaction and the role these interactions play in glomerular structure and function throughout development and in adulthood. In preliminary studies, we have identified a novel GBM-mesangial cell adhesion that contains the GBM protein nephronectin. We find that nephronectin is essential for development of the glomerular tuft, and also plays a role in maintenance of glomerular structure. We therefore propose to 1) determine the role of nephronectin in various stages of glomerulogenesis, 2) test its role in mediating stability of glomerular structure in mature kidneys, and 3) dissect the role of nephronectin-integrin signaling in cultured cells. Through these studies, we will greatly expand our understanding of GBM- mesangial cell interactions. Gaining molecular knowledge of these interactions and their function will be a critical step to understanding glomerular biology, and may contribute to directed therapies for glomerular disease.
Development of novel targeted therapies for kidney disease generally relies on an in depth understanding of the basic mechanisms that regulate normal kidney development, structure, and function. In the proposed research, we will study the role of specific cell-matrix interactions within glomeruli, the filtration units of the kidney. A deeper understanding of the molecular underpinning that direct cellular interactions in the glomerulus will provide new insight into the pathogenesis of kidney disease and unearth new targets for novel therapies.
