Physiological Role of the Vitamin A Transporter RBPR2 for Vision

项目摘要/摘要 膳食中维生素A/全反式视黄醇/全反式视黄醇在体内的分布对维甲酸的维持至关重要 在周围组织中发挥功能，并确保最佳视力。在人类中，饮食ROL在肠道中被吸收， 储存在肝脏中，并分泌到与血清视黄醇结合蛋白4(RBP4)结合的循环中。这个 循环膳食ROL结合的RBP4转运系统被认为在眼部具有特殊功能 人类依赖维生素A的视觉过程。因此，理解促进和 调节膳食维生素A的系统摄取和转运对眼部维甲酸的稳态具有重要意义 帮助设计旨在减轻与血清ROL缺乏相关的视网膜退行性疾病的策略 或者是过度的。这项提议的目的是确定一种新的维生素A转运体的生理作用， 视黄醇结合蛋白4受体2(RBPR2)在促进系统摄取膳食RBP4-ROL方面的作用 视力，并了解这种与眼睛相关的维生素A转运体的调节是否可以改善患者的视力 患有Stargardt病的患者患有维生素A代谢物的中毒性积聚。长期目标是 确定RBPR2在视网膜健康和疾病中与RBP4结合和ROL运输的机制。中环 假设RBPR2在缺乏STRA6的组织中与RBP4-ROL具有高亲和力结合，并且其 生理功能是确保饮食中足够的维生素A摄取和输送到眼睛的关键 持续支持愿景。这项提议的基本原理是，完成工作将填补知识 膳食维生素A如何从RBP4隔离到全身组织，在外周运输和储存的差距 缺乏STRA6的组织，在持续支持视力的过程中最终分配到眼睛。中环 将通过追求三个具体目标来检验假设，这三个目标将在：目标1]中确定 RBPR2用于RBP4结合和维生素A/ROL的吸收，目的2]确定RBPR2对 全身性RBP4-ROL对视觉的运输，以及目的3]确定Rbpr2活性的调节是否会减弱视网膜 退行性疾病。我们将通过结构分析的创新组合来实现这些目标， 生物化学、细胞生物学、生理学和新动物模型的产生旨在探索体内 RBPR2对ROL转运的要求对感光器健康、视力和减轻视网膜疾病的要求 各州。这项拟议的研究意义重大，因为它将首次确定促进 循环中RBP4-ROL的摄取、储存和转运进入眼内，并探讨是否对此类眼进行调制 相关的维生素A转运体可以改善遗传性视网膜退行性疾病患者的视力。这个 拟议研究的近期结果将提供信息，以提高对人类的理解 与血液维生素A稳态受损或维生素A过量有关的疾病状态，尤指失明 并可能为他们的预防和治疗提供概念。

PROJECT SUMMARY/ ABSTRACT 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.