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.

项目总结/摘要 饮食中维生素A/全反式视黄醇/ROL在全身的分布对维持类维生素A至关重要 在外周组织中发挥作用并确保最佳视力。在人类中，膳食ROL在肠中被吸收， 储存在肝脏中，并分泌到与血清视黄醇结合蛋白4（RBP 4）结合的循环中。的 循环饮食ROL结合的RBP 4转运系统已经被认为在眼部特异性地起作用 维生素A依赖的人类视觉过程。因此，了解促进和 调节膳食维生素A的全身摄取和转运对眼类维生素A的稳态是重要的， 帮助设计旨在减轻与血清ROL缺乏相关的视网膜变性疾病的策略 或过度。本提案的目的是确定一种新型维生素A转运蛋白的生理作用， 视黄醇结合蛋白4受体2（RBPR 2），促进饮食RBP 4-ROL的全身摄取， 视力，并了解调节这种眼睛相关的维生素A转运蛋白是否可以改善患者的视力 患有维生素A代谢物毒性积累的Stargardt病。长期目标是 确定视网膜健康和疾病中RBPR 2与RBP 4结合和ROL转运的机制。中央 假设RBPR 2在缺乏STRA 6的组织中对RBP 4-ROL具有高亲和力结合， 生理功能是至关重要的，以确保足够的膳食维生素A的吸收和交付的眼睛， 持续支持愿景。这一建议的基本原理是，完成将填补知识 饮食中维生素A如何从RBP 4隔离到全身组织中，在外周组织中运输和储存的差距 缺乏STRA 6的组织，用于最终分布到眼睛中以持续支持视力。中央 假设将通过追求三个具体目标进行测试，这些目标将：目标1]确定 RBPR 2用于RBP 4结合和维生素A/ROL摄取，目的2]确定RBPR 2用于RBP 4结合和维生素A/ROL摄取的生理作用。 [目的3]确定Rbpr 2活性的调节是否减弱视网膜色素变性， 退化性疾病我们将采用结构分析、 生物化学、细胞生物学、生理学和旨在探索体内 RBPR 2对ROL转运的要求，用于感光细胞健康、视力和减轻视网膜疾病 states.这项研究意义重大，因为它将首次确定促进 循环RBP 4-ROL的摄取、储存和转运入眼，并探讨这种眼调节是否 相关的维生素A转运蛋白可以改善患有遗传性视网膜变性疾病的人的视力。的 拟议的研究的近似结果将提供信息，将提高对人类的理解。 与血液维生素A稳态受损或维生素A过量相关的疾病状态，特别是失明 并可能产生预防和治疗的概念。