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: 10396810
• 负责人: Glenn P Lobo
• 金额: $ 33.83万
• 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/10396810
• 关键词: Affect; Affinity; All-Trans-Retinol; Anabolism; Animal Model; Attenuated; Back; Binding; Binding Proteins; Binding Sites; Biochemistry; Biogenesis; Biological; Biological Assay; Blindness; Blood; Blood Circulation; Cell Culture Techniques; Cell Death; Cellular biology; Co-Immunoprecipitations; Dietary Carotenoid; Disease; Docking; Ensure; Extrahepatic; Eye; Fasting; Genes; Goals; Health; High Pressure Liquid Chromatography; Homeostasis; Human; Impairment; In Vitro; Inherited; Intestines; Kinetics; Knockout Mice; Knowledge; Ligands; Lipofuscin; Liver; Measures; Mediating; Mus; Mutation; Ocular Pathology; Organ; Outcome; Patients; Peripheral; Phenotype; Photoreceptors; Physiological; Physiology; Play; Prevention therapy; Process; Proteins; Public Health; RBP4 gene; Regulation; Reporting; Research; Retina; Retinal Degeneration; Retinal Diseases; Retinoids; Role; Serum; Signal Transduction; Site-Directed Mutagenesis; Small Intestines; Spectrum Analysis; Structural Models; Structure; Supplementation; Surface Plasmon Resonance; System; Testing; Time; Tissues; Toxic effect; Tretinoin; Vision; Visual; Vitamin A; Vitamin A Deficiency; aged; base; 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：饮食中维生素A/All-Trans视黄醇/ROL在整个体内的分布对于维持至关重要 类视黄素功能在周围组织中并确保最佳视力。在人类中，饮食维生素A被吸收 小肠，储存在肝脏中，并分泌到与血清视黄醇结合蛋白4结合的循环中 （RBP4-ROL）。一种用于全身RBP4-ROL摄取，存储和运输的受体介导的系统是必不可少的 不仅可以确保可获得最佳的眼类视黄素信号的光感受器功能，还可以防止 细胞毒性与过度的类维生素性积累有关。 Stra6，唯一已知的循环受体 眼睛中的ROL结合RBP4在系统组织中未表达，以促进RBP4-的吸收 ROL。这表明在此类组织中存在额外的维生素A转运蛋白。目标的目标 建议是1]，以确定新型维生素A转运蛋白，视黄醇结合蛋白4 受体2（rbpr2）促进饮食中饮食ROL结合的rbp4的全身摄取，并研究2] 如果对这种相关的ROL转运蛋白的调节可能会限制有毒性类维生素类似的底物可用性 生物发生，从而改善遗传性视网膜退行性疾病患者的视力。长期目标 是为了确定RBPR2在视网膜健康中的RBP4结合和ROL运输的生理机制和 疾病状态。中心假设是rbpr2在无液体中对RBP4-rol具有高亲和力结合 Stra6的生理功能对于确保和调节饮食维生素的吸收和递送至关重要 为了支持视觉。该提议的基本原理是完成将填补知识 饮食中维生素A如何被RBP4隔离到全身组织中的空白，并存储在 缺乏Stra6的外围组织，最终分布到视力之眼。中心假设将是 通过追求特定目标1：确定RBPR2功能的三个特定目标来测试 维生素A运输；特定目标2：确定RBPR2在全身RBP4-ROL中的生理作用 视力运输；和特定目标3：确定RBPR2活性的调节是否减弱遗传性视网膜 退化性疾病。我们将使用结构分析的创新组合来追求这些目标， 生物化学，细胞生物学，生理学和新型动物模型旨在探索体内要求 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 意义重大，因为它将首次确定影响循环rbp4-rol摄取的机制， 储存和运输到眼睛中，并探索旨在调节此类与眼睛相关的Rol-的策略 用于改善遗传性视网膜疾病人类视力的转运蛋白。接近的结果 拟议的研究将提供有关新型ROL转运蛋白RBPR2的信息，该信息将改善理解 人类疾病状态，尤其是失明，与血液维生素A稳态或眼部有关 维生素A多余，可以产生预防和治疗的概念。