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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK025373-09
Application #
3227352
Study Section
Biochemistry Study Section (BIO)
Project Start
1979-04-01
Project End
1988-07-31
Budget Start
1987-08-01
Budget End
1988-07-31
Support Year
9
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of South Carolina at Columbia
Department
Type
Schools of Arts and Sciences
DUNS #
111310249
City
Columbia
State
SC
Country
United States
Zip Code
29208
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Chroneos, Z C; Baynes, J W; Thorpe, S R (1995) Identification of liver endothelial cells as the primary site of IgM catabolism in the rat. Arch Biochem Biophys 319:63-73
Thorpe, S R; Baynes, J W (1994) Residualizing glycoconjugates: biologically inert tracers for studies on protein endocytosis and catabolism. Methods Enzymol 242:3-17
Potter, D; Chroneos, Z C; Baynes, J W et al. (1993) In vivo fate of hemopexin and heme-hemopexin complexes in the rat. Arch Biochem Biophys 300:98-104
Thorpe, S R; Baynes, J W; Chroneos, Z C (1993) The design and application of residualizing labels for studies of protein catabolism. FASEB J 7:399-405
Wells-Knecht, M C; Huggins, T G; Dyer, D G et al. (1993) Oxidized amino acids in lens protein with age. Measurement of o-tyrosine and dityrosine in the aging human lens. J Biol Chem 268:12348-52
Bichler, J; Baynes, J W; Thorpe, S R (1993) Catabolism of hirudin and thrombin-hirudin complexes in the rat. Biochem J 296 ( Pt 3):771-6
Huggins, T G; Wells-Knecht, M C; Detorie, N A et al. (1993) Formation of o-tyrosine and dityrosine in proteins during radiolytic and metal-catalyzed oxidation. J Biol Chem 268:12341-7
Ord, J M; Hasapes, J; Daugherty, A et al. (1992) Imaging of thrombi with tissue-type plasminogen activator rendered enzymatically inactive and conjugated to a residualizing label. Circulation 85:288-97
Huggins, T G; Staton, M W; Dyer, D G et al. (1992) o-Tyrosine and dityrosine concentrations in oxidized proteins and lens proteins with age. Ann N Y Acad Sci 663:436-7

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