Physiological Role of the Vitamin A Transporter RBPR2 for Vision

Summary: 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 vitamin A is absorbed in the small intestine, stored in the liver, and secreted into circulation bound to serum retinol binding protein 4 (RBP4-ROL). A receptor-mediated system for systemic RBP4-ROL uptake, storage and transport is essential not only to ensure availability for optimal ocular retinoid signaling for photoreceptor function, but also to prevent cellular toxicity associated with excessive retinoid accumulation. STRA6, the only known receptor for circulatory ROL bound RBP4 in the eye, is not expressed in systemic tissues proposed to facilitate the uptake of RBP4- ROL. This indicates the existence of additional vitamin A transporters in such tissues. The objectives of this proposal are 1] 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 ROL bound RBP4 for vision, and 2] to investigate if modulation of such eye related ROL transporters could limit substrate availability required for toxic retinoid biogenesis and thus improve vision in patients with inherited retinal degenerative diseases. The long-term goal is to identify the physiological mechanisms of RBPR2 for RBP4 binding and ROL transport in retinal health and disease states. 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 and regulate dietary vitamin A uptake and delivery to the eye in the 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 for vision. The central hypothesis will be tested by pursuing three specific aims that will in Specific Aim 1: Determine the functionality of RBPR2 for vitamin A transport; Specific Aim 2: Determine the physiological role of RBPR2 for systemic RBP4-ROL transport in vision; and Specific Aim 3: Determine if modulation of Rbpr2 activity attenuates inherited retinal degenerative diseases. We will pursue these aims using an innovative combination of structural analysis, biochemistry, cell biology, physiology and novel animal models aimed at exploring the in vivo requirements of RBPR2 for ROL transport for photoreceptor health, vision and in retinal disease. The proposed research is significant because it will determine for the first time the mechanisms influencing circulatory RBP4-ROL uptake, storage and transport into the eye, and explore strategies aimed at modulation of such eye related ROL- transporters for improving vision in humans with inherited retinal diseases. The proximate outcome of the proposed research will provide information on a novel ROL transporter, RBPR2, that will improve understanding of human disease states, particularly blindness, associated with impaired blood vitamin A homeostasis or ocular vitamin A excess and could yield concepts for their prevention and therapy.