Studies on the molecular and cellular regulation of the intestinal absorption processes of water-soluble vitamins have been limited due in part to lack of suitable molecular probes/cell models that are needed to address these issues. This situation has begun to change in recent years with the cloning and molecular characterization of the transport systems involved in the intestinal absorption of these essential nutrients, and the availability of appropriate cell models/tools.
The aims of the present proposal are to delineate the molecular and cellular mechanisms involved in the regulation of the intestinal absorption process of vitamin H, i.e., biotin, a process that has been recently shown to be also utilized by two other functionally unrelated nutrients, namely the vitamin pantothenic acid and the metabolically important antioxidant lipoate [for this reason the system involved is also being referred to now as the sodium- dependent multivitamin transport system, or SMVT]. Biotin is an essential micro-nutrient whose importance to normal health and well-being is underscored by the serious clinical abnormalities that results from its deficiency which include neurological disorders and growth retardation. Humans and other mammals can not synthesize biotin, and thus, must obtain the vitamin from exogenous sources via intestinal absorption. The mechanism of intestinal biotin absorption has been characterized by us and others and evidence was obtained indicating that the process is regulated by dietary biotin levels and by ontogeny. Very little, however, is known about the molecular and cellular mechanisms involved in this regulation. The recent cloning and molecular characterization of the intestinal biotin uptake system has assisted us in initiating studies to address these issues. In preliminary studies, we have obtained evidence that suggests possible involvement of transcriptional regulatory mechanism(s) in the regulation of intestinal biotin transport by extracellular biotin levels. We have also delineated the sequence of a 4.3 kb genomic DNA that is of relevance to our effort of characterizing the 5' regulatory region of the transporter gene. Based on this background, our specific aims in this proposal are: 1) to characterize the molecular/cellular mechanism(s) involved in the regulation of the intestinal biotin absorption process by dietary (extracellular) biotin levels, 2) to clone and characterize the 5'-regulatory region of the gene of the biotin transporter SMVT, and 3) to characterize the molecular mechanism(s) involved in the ontogenic regulation of the intestinal biotin transport process. The rat will be used as the experimental animal model in these studies. Results of these investigations will provide information that are of significant physiological and nutritional importance to both adult and the developing newborn regarding the molecular and cellular regulation of the intestinal absorption process of biotin in particular, and that of pantothenic acid and lipoate in general. These results should also contribute toward our understanding of regulation of SMVT function in other tissues that have been shown to express this transport system.
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