Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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The central theme has been to characterize the responses of the glomerular mesangial cell (MC) to injury in vivo that lead to either progressive scarring or repair. During the initial grant period, the applicant characterized three major responses of the MC to injury: a PDGF- and bFGF-mediated proliferation, a phenotype change to a "myofibroblast", and a stimulation of matrix synthesis. This proposal will study a fourth response of MC to injury, i.e., MC migration. The hypothesis to be tested is that mesangial cell migration is critical in both glomerular disease and development of the repair and formation of the mesangium. To date indirect evidence has been provided for MC migration in vivo. The investigator and his colleagues developed a technique that allows them to document and quantitate MC migration in vivo. Using this method, they have documented MC migration in the Thy 1 model of mesangiolytic injury. They also showed that the mesangium is repopulated by an extraglomerular mesangial precursor, which invades the hilus and undergoes subsequent cell divisions and migration to eventually reconstitute the entire MC population. Similar preliminary data has been obtained in the developing rat glomerulus. They now propose to extend these studies. In Aim 1 they will document the kinetics and magnitude of the mesangial migratory response in the Thy 1 model and in another model of mesangiolytic injury, that induced by Habu snake venom. In Aim 2 they will determine some of the key factors that may mediate the migratory response, including PDGF, bFGF, thrombospondin 1, angiotensin II and others. The consequence of blocking these factors on other aspects of the mesangial response will be assessed, in order to determine if blocking mesangial migration can be correlated with other structural or functional changes. In Aim 3 they will address MC migration in development, and determine if the migration is mediated by PDGF or thrombospondin 1, and what the consequences are for glomerular development if the MC precursors are eliminated by anti-Thy 1 antibody. It is hoped that these studies will clarify the role of MC migration in both glomerular disease and development, and may provide new insights into the mechanisms of glomerular repair.
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