The overall objectives of this project are: 1) to examine the effect of streptozotocin-diabetes on the biochemistry of basement membrane components; 2) to study the effect of diabetes on the in vivo synthesis and turnover of specific collagen and non-collagen moieties of glomerular basement membrane; 3) to evaluate the effect of insulin treatment on changes in basement membrane metabolism identified in the foregoing studies; and 4) to examine the manner in which glucose and growth hormone modulate glomerular and lens capsule basement membrane synthesis and structure-function relationships. Glomerular and lens capsule basement membranes will be purified from control, streptozotocin-diabetic, and growth hormone or insulin treated rats, either after in vivo radiotracer injection or incubation in vitro of isolated glomeruli or lenses with appropriate radiolabeled precursor. In vivo studies will follow the biosynthesis and turnover of procollagen, proteoglycan, and glycoprotein. In vitro studies will assess the effect of glucose and growth hormone on the production specific basement membrane components including glycosaminoglycan, laminin, and entactin. Analytic studies will probe the manner in which increased non-enzymatic glycosylation in diabetes influences basement membrane organization by examining collagen cross-link formation, solubility, polymerization, and lysyloxidase-catalyzed aldehyde formation. The results of these studies are expected to advance our understanding of the pathogenesis of diabetic microangiopathy and of the defects in the capillary filtration barrier which contribute to complications of diabetes.
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