RENAL RESPONSE TO INJURY

本提案是一项多学科的研究工作

This proposal is a multidisciplinary research effort which is directed at better understanding the renal response to several forms of glomerular injury that lead to chronic renal failure. The Center will support research on two molecules which have not been previously associated with renal disease (SPARC is an important regulator of glomerular cell proliferation and attachment and that increased osteopontin (OPN) in tubules mediates interstitial macrophage infiltration leading to fibrosis and progressive renal disease. In Project 1, Drs. Bassuk and Sage will explore the structural basis for properties of the SPARC molecule that may modulate tahe mesangial response to injury including effects on mesangial cell morphology, attachment to matrix, proliferation and growth. In Project 2, Drs. Couser and Sage will assess the role of increased SPARC expression in glomerular mesangial and epithelial cells in vivo as this relates to modulation of cell proliferation and alterations in cell matrix interaction. In Project 3, Dr. Giachelli will conduct basic studies of the factors which regulate OPN chemotaxis and adhesive functions and of the mechanisms which regulate OPN gene expression in several cell types at a molecular level. In Project 4, Drs. Giachelli and Johnson will test the hypothesis that OPN is an important mediator of progressive renal disease by performing sequential studies of the site and extent of OPN protein and MRNA expression as it relates to various other cellular and structural findings in the mesangioproliferative, aminonucleoside and cyclosporin-induced models of progressive renal disease, determine if OPN expression is mediated by AII and assess the consequences of blocking OPN activity in vivo with neutralizing antibodies or specific blocking peptides. In Project 5, Dr. Schwartz will study the mitogenic factors involved in stimulation of microvascular smooth muscle proliferation in hypertensive injury, examine the expression of genes characteristic of injured neointima in large vessels as they relate to histopathologic changes in kidney microvessels in response to hypertensive injury and examine the factors which regulate recovery of an injured renal microvessel from hypertensive injury. In the Morphology and Clinical Application Core, Dr. Alpers will extend the observations made in projects 1-5 to studies of normal and diseased human kidney tissue. This Center will be administered through an Administrative Core directed by Dr. Couser.