Vitamin A is transported in blood bound to a complex of 2 plasma proteins: retinol binding protein and prealbumin. The overall goal of this application is to decipher the mechanism by which retinol is taken up from blood by target cells. THe spontaneous rates of the individual steps that constitute the transfer process will be measured. The data will be used to determine what factor(s) limit and regulate the rate of uptake of vitamin A. Rates of uptake of retinol from the binding site on the serum binding proteins will be measured using: 1) """"""""model cells"""""""" comprised of unilamellar vesicles containing several protein components that are candidates for facilitating uptake. 2) isolated pigment epithelium cells. These measurements will clarify whether uptake is facilitated by a specialized biochemical mechanism in the plasma membranes of target cells and which specific step is facilitated, or whether uptake occurs spontaneously. The results are expected to point at ways to modulate uptake. This is important because retinoids may be useful in the treatment and prevention of cancer. However, retinol toxicity generally prevents use of effective doses. Detailed understanding of the delivery process may give clues for targeting to specific tissues. The interactions of physiologic derivatives of vitamin A (retinol, retinoic acid and retinaldehyde) with the biological compartments that have a high affinity for them will be studied in detail. These compartments are: binding proteins, in plasma and in cytosol, and biological membranes. These studies should establish the factors that determine the distribution of retinoids in vivo, and clarify the chemical basis for their interactions in various environments.
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