Physiological Role of the Vitamin A Transporter RBPR2 for Vision

维生素 A 转运蛋白 RBPR2 对视觉的生理作用

• 批准号: 10551503
• 负责人: Glenn P Lobo
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551503
• 关键词: Affinity; All-Trans-Retinol; Animal Model; Attenuated; Binding; Biochemistry; Blindness; Blood; Blood Circulation; Cellular biology; Disease; Ensure; Eye; Generations; Genes; Goals; Health; Homeostasis; Human; Impairment; Inherited; Intestines; Knowledge; Liver; Mutation; Outcome; Patients; Peripheral; Phenotype; Photoreceptors; Physiological; Physiology; Play; Prevention therapy; Process; RBP4 gene; Research; Retina; Retinal Degeneration; Retinal Diseases; Retinoids; Role; Serum; Stargardt' s disease; System; Testing; Time; Tissues; Vision; Vitamin A; Vitamin A Deficiency; design; dietary; human disease; improved; in vivo; innovation; novel; receptor; retinol binding protein receptor; uptake; visual cycle

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.

项目概要/摘要 膳食维生素 A/全反式视黄醇/ROL 在全身的分布对于维持类视黄醇至关重要 在周围组织中发挥作用并确保最佳视力。在人类中，饮食中的 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 循环膳食 ROL 结合的 RBP4 转运系统被认为在眼部发挥特殊作用 人类视觉过程依赖于维生素 A。因此，了解促进和 调节膳食维生素 A 的全身摄取和运输对于眼视黄醇稳态具有重要意义， 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 或过量。该提案的目的是确定新型维生素 A 转运蛋白的生理作用， 视黄醇结合蛋白 4 受体 2 (RBPR2)，促进膳食 RBP4-ROL 的全身摄取 视力，并了解调节此类与眼睛相关的维生素 A 转运蛋白是否可以改善患者的视力 患有 Stargardt 病，因维生素 A 代谢物中毒积累。长期目标是 确定 RBPR2 在视网膜健康和疾病中与 RBP4 结合和 ROL 转运的机制。中央 假设是 RBPR2 在缺乏 STRA6 的组织中与 RBP4-ROL 具有高亲和力结合，并且其 生理功能对于确保充足的膳食维生素 A 摄取和输送到眼睛至关重要 愿景的持续支持。该提案的基本原理是完成将填补知识 膳食维生素 A 如何从 RBP4 中隔离到全身组织、运输和储存在外周组织中的差距 缺乏STRA6的组织，最终分布到眼睛以持续支持视力。中央 将通过追求三个具体目标来检验假设： 目标 1] 确定 RBPR2 用于 RBP4 结合和维生素 A/ROL 摄取，目标 2] 确定 RBPR2 的生理作用 系统性 RBP4-ROL 视觉传输，目标 3] 确定 Rbpr2 活性的调节是否会减弱视网膜 退行性疾病。我们将利用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、生理学和旨在探索体内的新型动物模型的生成 RBPR2 对 ROL 运输的要求，以促进光感受器健康、视力和减轻视网膜疾病 州。拟议的研究意义重大，因为它将首次确定促进机制 循环RBP4-ROL摄取、储存和运输到眼睛中，并探索是否对这种眼睛进行调节 相关的维生素 A 转运蛋白可以改善患有遗传性视网膜退行性疾病的人类的视力。这 拟议研究的近期结果将提供有助于增进对人类的了解的信息 与血液维生素 A 稳态受损或维生素 A 过量相关的疾病状态，尤其是失明 并可以产生预防和治疗的概念。