The central focus of this Program Project is to understand the mechanisms by which vitamin A acts to maintain optimal growth and health of the organism. For vitamin A to act in maintaining growth and health, it must be obtained from the diet; undergo transport, storage and mobilization processes; and be metabolized to active forms. Finally, its active forms must interact with transcription factors and the transcription machinery to regulate gene expression. Diets deficient in vitamin A result in characteristic abnormal development and disease in virtually all animals, including humans. However, the molecular mechanisms of action of vitamin A following its provision in the diet are not well understood. To elucidate the role of vitamin A in maintaining health, it is necessary to integrate an understanding of dietary vitamin A intake, vitamin A metabolism and the molecular events important to regulating responsive genes. The five individuals research projects which compose the Program Project will explore in the mouse model different aspects of vitamin A transport, storage and metabolism, the factors and processes which influence vitamin A uptake by cells and tissues or the molecular processes through which vitamin A acts to regulate gene expression and how intake of different levels of vitamin A from the diet influences each of these. Together, the five projects constitute a research program which has a major objective delineating a comprehensive and unified view of vitamin A physiology and vitamin A actions. One of the themes for this Program Project is exploring tissue-specific differences both in vitamin A delivery and processing and in the mechanisms through which vitamin A acts to regulate cellular homeostasis. A second them is understanding the role of vitamin A and its metabolites in the regulation of gene expression, again, in a tissue-specific manner. A third common theme for the Program is to ask how the modulation of dietary intake of vitamin A through purified diets will affect various aspects of vitamin A physiology and actions in the mouse model. Each project employs induced mutant, both transgenic and knockout, mice in its investigations: thus, the use of genetic approaches in mouse models is a fourth common and central theme for this Program. This Program is unique in the breadth of scope in which the function of dietary retinol will be addressed--from the uptake and metabolism of a micronutrient to its function at the level of specific target genes.
