A broad research program is proposed dealing with several aspects of the metabolism of retinoids. This program seeks to acquire fundamental new information about the metabolism, the metabolic regulation, and the functions and roles of retinoids and of retinoid-binding proteins. The results should be relevant in several ways to human biology and disease. Two major projects are proposed. Project One, on retinoid-binding protein (RBP) metabolism and vitamin A transport, will explore the metabolism, regulation, chemistry, and functions of plasma RBP. The project is organized as 9 Specific Aims that propose to study: (1) the cellular localization of RBP mRNA by in situ hybridization; (2) the regulation of RBP synthesis and secretion by cultured hepatocytes; (3) RBP turnover in the rat in vivo, and effects of retinol deficiency on RBP turnover and catabolism in liver; (4) RBP secretion by the liver, including the intracellular pathways and processes involved and their regulation; (5) the tissue sites of catabolism of RBP and transthyretin (TTR); (6) cell surface receptors for RBP; (7) the functional domains of RBP by means of monoclonal antibodies directed at different epitopes on RBP; (8) the regulation of the induction of expression of the RBP gene during development; and (9) DNA polymorphisms in or near the human RBP gene, and their possible physiological significance. Project Two, on the intracellular binding proteins for retinol (CRBP) and retinoic acid (CRABP) will explore the metabolism, regulation, and biological roles of the cellular retinoid-binding proteins. The project is organized as 8 Specific Aims that propose: (1) to prepare a cDNA clone for rat CRBP; and (2) to prepare specific cDNA clones for CRABP; and then to study: (3) the synthesis and metabolism of CRBP and CRABP in a variety of tissues in the rat; (4) the effects of nutritional and metabolic perturbations on the levels of CRBP mRNA and CRABP mRNA in rat tissues; (5) the cellullar localization of CRBP mRNA and CRABP mRNA by in situ hybridization; (6) the tissue levels of CRBP mRNA and CRABP mRNA during fetal development; (7) the tissue specific expression of CRBP and CRABP at the molecular level; and (8) the possible occurrence and significance of post-translational modifications of CRBP and CRABP within cells.
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