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: 10655469
• 负责人: Glenn P Lobo
• 金额: $ 34.88万
• 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/10655469
• 关键词: Acceleration; Affect; Affinity; All-Trans-Retinol; Anabolism; Animal Model; Attenuated; Back; Binding; Binding Proteins; Binding Sites; Biochemistry; Biogenesis; Biological; Biological Assay; Blindness; Blood; Cell Culture Techniques; Cell Death; Cellular biology; Circulation; Co-Immunoprecipitations; Dietary Carotenoid; Disease; Docking; Ensure; Extrahepatic; Eye; Fasting; Genes; Goals; Health; Hepatic Tissue; High Pressure Liquid Chromatography; Homeostasis; Human; Impairment; In Vitro; Inherited; Intestines; Kinetics; Knockout Mice; Knowledge; Ligands; Lipofuscin; Literature; Liver; Measures; Mediating; Mus; Mutation; Ocular Pathology; Organ; Outcome; Patients; Peripheral; Phenotype; Photoreceptors; Physiological; Physiology; Play; Prevention; Process; Proteins; Public Health; RBP4 gene; Receptor-Interacting Serine/Threonine Protein Kinase 2; Regulation; Reporting; Research; Retina; Retinal Degeneration; Retinal Diseases; Retinoids; Role; Serum; Signal Transduction; Site-Directed Mutagenesis; Small Intestines; Spectrum Analysis; Structural Models; Supplementation; Surface Plasmon Resonance; System; Testing; Time; Tissues; Toxic effect; Tretinoin; Vision; Vitamin A; Vitamin A Deficiency; Zebrafish; absorption; aged; cytotoxic; deprivation; design; dietary; dietary excess; extracellular; gene product; human disease; improved; in vivo; innovation; novel; prevent; receptor; retinol binding protein receptor; uptake; visual cycle

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.

摘要：膳食中维生素A/全反式视黄醇/ROL在体内的分布对维持 维甲酸在外周组织中的功能，并确保最佳视力。在人类中，饮食中的维生素A被 储存在肝脏中的小肠，分泌到循环中，与血清视黄醇结合蛋白4结合 (RBP4-ROL)。受体介导的全身性RBP4-ROL摄取、储存和转运系统是必不可少的 不仅是为了确保获得最佳的视黄醇信号来实现光感受器功能，而且还为了防止 与过量维甲酸蓄积有关的细胞毒性。STRA6，已知的唯一循环受体 ROL结合的RBP4在眼睛中，在系统组织中不表达，被认为有助于摄取RBP4- 罗尔。这表明在这些组织中存在额外的维生素A转运体。这样做的目的是 建议1]确定一种新的维生素A转运体--视黄醇结合蛋白4的生理作用 受体2(RBPR2)在促进饮食ROL结合的RBP4系统摄取视觉方面的作用，以及2]研究 如果这种眼睛相关的ROL转运蛋白的调节可能会限制有毒维甲酸所需的底物的可用性 生物发生，从而改善遗传性视网膜变性疾病患者的视力。长期目标 目的是确定RBPR2与RBP4结合和ROL运输在视网膜健康和 疾病状态。中心假设是RBPR2在缺失组织中与RBP4-ROL具有高亲和力结合 STRA6的生理功能对保证和调节膳食中维生素A的摄取和转运至关重要 用眼睛来支撑视力。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是如何从RBP4隔离到全身组织中，运输和储存在 缺乏STRA6的外周组织，用于最终分配到眼睛以获得视力。中心假设将是 通过追求三个特定目标进行测试，这三个特定目标将在特定目标1中：确定RBPR2的功能 维生素A转运；特定目标2：确定RBPR2对全身RBP4-ROL的生理作用 视觉运输；和特定目标3：确定Rbpr2活性的调节是否减弱遗传性视网膜 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、生理学和旨在探索体内需求的新型动物模型 RBPR2用于光感受器健康、视力和视网膜疾病的ROL运输。拟议的研究是 因为它将首次确定影响循环RBP4-ROL摄取的机制， 眼睛的储存和运输，并探索旨在调节这种与眼睛相关的ROL的策略。 遗传性视网膜疾病患者改善视力的转运体。这次选举的近期结果是 拟议的研究将提供关于一种新的ROL转运体RBPR2的信息，这将提高人们对 人类疾病的一种状态，尤其是失明，与血液中维生素A稳态受损或眼睛受损有关 维生素A过量，并可为他们的预防和治疗提供概念。