Distribution of dietary vitamin A/all-trans retinol/ROL throughout the body is critical to maintain retinoid function in peripheral tissues and to ensure optimal vision. In humans, dietary ROL is absorbed in the intestine, stored in the liver, and secreted into the circulation bound to serum retinol binding protein 4 (RBP4). The circulatory dietary ROL bound RBP4 transport system has been suggested to specifically function in the ocular vitamin A- dependent processes of vision in humans. Thus, an understanding of mechanisms that facilitate and regulate the systemic uptake and transport of dietary vitamin A for ocular retinoid homeostasis are significant, to help design strategies aimed at attenuating retinal degenerative diseases associated with serum ROL deficiency or excess. The objectives of this proposal are to determine the physiological role a novel vitamin A transporter, the retinol binding protein 4 receptor 2 (RBPR2), in facilitating the systemic uptake of dietary RBP4-ROL for vision, and to understand if modulation of such eye related vitamin A transporters could improve vision in patients with Stargardt disease suffering from toxic accumulation of vitamin A metabolites. The long-term goal is to identify the mechanisms of RBPR2 for RBP4 binding and ROL transport in retinal health and disease. The central hypothesis is that RBPR2 has high affinity binding for RBP4-ROL in tissues devoid of STRA6 and that its physiological function is critical to ensure adequate dietary vitamin A uptake and delivery to the eye in the continuous support of vision. The rationale underlying this proposal is that completion will fill the knowledge gap of how dietary vitamin A is sequestered into systemic tissues from RBP4, transported and stored in peripheral tissues lacking STRA6, for eventual distribution to the eye in the continuous support of vision. The central hypothesis will be tested by pursuing three specific aims that will in:
Aim 1 ] Determine the functionality of RBPR2 for RBP4 binding and vitamin A/ROL uptake, Aim 2] Determine the physiological role of RBPR2 for systemic RBP4-ROL transport for vision, and Aim 3] Determine if modulation of Rbpr2 activity attenuates retinal degenerative diseases. We will pursue these aims using an innovative combination of structural analysis, biochemistry, cell biology, physiology and generation of novel animal models aimed at exploring the in vivo requirements of RBPR2 for ROL transport for photoreceptor health, vision and in attenuating retinal disease states. The proposed research is significant, because it will determine for the first time the mechanisms facilitating circulatory RBP4-ROL uptake, storage and transport into the eye, and explore whether modulation of such eye related vitamin A transporters could improve vision in humans with inherited retinal degenerative diseases. The proximate outcome of the proposed research will provide information that will improve understanding of human disease states, particularly blindness, associated with impaired blood vitamin A homeostasis or vitamin A excess and could yield concepts for their prevention and therapy.
In humans, either prolonged dietary vitamin A deficiency (VAD) or inherited mutations in retinoid/visual cycle genes manifests in similar retinal degenerative phenotypes, eventually leading to vision loss and blindness. This study proposes to test the novel hypothesis that the systemically expressed retinol binding protein receptor 2 (RBPR2) facilitates and regulates dietary vitamin A transport and hence physiologically plays an important role in photoreceptor health and vision. At the completion of this project, a mechanistic understanding of RBPR2 function for ocular vitamin A homeostasis will help design strategies aimed at modulation of such eye-related ROL transporters for improving vision in humans with inherited retinal diseases.
