There are two general objectives of this research: (1) to continue the development, evaluation and application of residualizing labels for determining the sites of catabolism of plasma proteins and, (2) to characterize the molecular mechanisms regulating plasma protein catabolism at those sites, in health and disease. We will continue to study the catabolism of albumin and immunoglobulins (IgG) in the rat in vivo, and in vitro, as our model system. At the macroscopic level tissues active in degradation of these proteins are identified by measuring the accumulation of metabolically inert radioactive labels which are covalently bound to protein and residualize in tissue lysosomes after protein breakdown. We have recently introduced dilactitol-125I-tyramine as such a residualizing tracer: we plan to improve this technology by developing larger, more hydrophilic glycoconjugate labels. At the same time we will initiate studies on the rates of exocytosis of these residualizing labels and related oligosaccharides as a function of molecular weight by cells in culture. The regulation of albumin and IgG catabolism in diabetes and starvation will be investigated in an effort to understand the role of hormonal regulation and physiological changes in protein distribution volume in the regulation of their catabolism, as well as test the hypothesis that the rate of albumin catabolism is dependent on its degree of saturation with fatty acids. At the microscopic level individual cell types involve in albumin and IgG turnover will be identified using autoradiographic techniques. Work to date has identified fibroblasts in muscle and skin as a major site of albumin, and possibly IgG, turnover. In vitro studies using these cells will be carried out to distinguish between various kinetic models for the regulation of albumin catabolism, to characterize cellular receptors participating in this process and to identify structural features of the protein molecules which are involved in the regulation of their catabolism.
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