The essential role of vitamin A for the vertebrate eye has long been known because deficiency in or excess of this vitamin can impair eye development and function. Vitamin A is the precursor for at least two critical metabolites, 11-cis-retinal, the chromophore of visual G-protein-coupled receptors, and retinoic acid, a ligand for nuclear receptors. Since retinoids cannot be synthesized de novo by humans, dietary precursors must be absorbed by the intestine and metabolically converted. The converted retinoids must then be transported within the body for storage and delivered to target tissues such as the eyes. This process evidently depends on specific transporters and binding proteins. These components have recently attracted broad scientific and clinical interest since they are associated with diseases as diverse as type 2 diabetes and the fatal Matthew- Wood syndrome. Yet our knowledge of the pathology of these diseases is scant due to a lack of studies in homologous mammalian animal models. Such study would contribute to our understanding of the biochemistry of vitamin A transport as well as the regulatory mechanisms that govern retinoid homeostasis. The long-term objective of the proposed studies is to analyze two key steps affecting ocular retinoid metabolism: the intestinal absorption and metabolic conversion of b,b-carotene to retinol and the uptake of b,b-carotene-derived retinol into the eyes.
In Aim 1, we will address the role of the intestine specific homeobox transcription factor ISX that suppresses Srb1 and Bcmo1 gene activities which respectively encode a carotenoid transporter and the key enzyme for b,b-carotene conversion into retinoids. By genetic dissection, we will analyze the molecular basis of b,b-carotene absorption and conversion into retinoids and the regulation of this pathway. For this purpose, we will study b,b-carotene metabolism and retinoid homeostasis in Isx, Srb1 and Bcmo1 single and compound knockout mice. Promoter/reporter gene studies will be performed to elucidate the molecular details of this regulation including the role of retinoic acid in this process.
In Aim 2, we will establish knockout mice lacking STRA6 (stimulated by retinoic acid 6) protein to study the metabolic basis of the fatal Matthew-Wood syndrome. We also will generate compound knockouts lacking both STRA6 and the serum retinol binding protein 4 (RBP4) to test for the hypothesis that RBP4 triggers the pathological alterations seen in STRA6- deficiency. Furthermore, we will analyze the role retinoic acid in regulating blood retinol homeostasis in the different mouse mutants. These studies will provide new insights into retinoid metabolism and the control of retinoid homeostasis which will improve understanding of human disease states caused by disturbances in this process and may provide concepts for their prevention and/or therapy.
/ STATEMENT Retinoids (vitamin A and its derivatives) play an essential role for eye development and function. Ocular retinoid uptake is a homeostatic process that evidently depends on specific transporters and binding proteins. These components have recently attracted broad scientific and clinical interest since they are associated with diseases including the fatal Matthew-Wood syndrome. Yet our knowledge of the underlying pathological processes is scant due to a lack of studies in homologous animal models. Therefore, the long-term objective of our research is to elucidate the pathway for ocular retinoid homeostasis by genetic dissection in mouse models. This information will improve understanding of human disease states caused by disturbances in retinoid homeostasis and may provide concepts for their prevention and/or therapy.
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