Role of a3a4a5(IV) collagen in podocyte behavior

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): Podocytes, endothelial cells, and the glomerular basement membrane (GBM) are the key components of the glomerular filtration barrier. The long term goal of this project is to understand how the composition of collagen IV in the GBM influences the behavior of podocytes (glomerular epithelial cells). Type IV collagen is expressed as an a1a1a2(IV) network in the immature GBM but is replaced by the a3a4a5(IV) network in the mature GBM. Failure to switch to the mature network due to mutations in any of the a3, a4 or a5 chains leads to Alport syndrome in humans and Alport-like phenotype in mouse and dog models of the disease. The mechanism whereby the a3a4a5(IV) collagen is required for the long term maintenance of the renal glomerular function is not known. We hypothesize that type IV collagen of the GBM, synthesized by podocytes, in turn provides signals to podocytes through integrins or other cellular receptors, which are required to maintain the appropriate podocyte function. To test this hypothesis, we will pursue two specific aims: (1) to express, isolate, and characterize the a3a4a5(IV) collagen in vitro; and (2) To define the influence of the a3a4a5(IV) collagen on the podocytes phenotype, including comparison of podocytes adhesion and migration on a3a4a5(IV) vs. a1a1a2(IV) collagen, identification of the podocyte integrins interacting with a3a4a5(IV) collagen, and identification of collagen IV domains that interact with podocytes. The successful completion of this project would help improve our understanding of the molecular defects in Alport syndrome, while broadening the applicant's research expertise and preparing her for the transition to an independent investigator status.