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.

总结：饮食中维生素A/全反式视黄醇/ROL在整个身体中的分布对于维持 视色素在外周组织中起作用，并确保最佳视力。对于人类来说，膳食维生素A被吸收 小肠，储存在肝脏中，并分泌到循环中，与血清视黄醇结合蛋白4结合 （RBP4-ROL）。受体介导的系统对全身RBP 4-ROL的摄取、储存和转运至关重要 不仅确保光感受器功能的最佳眼类视色素信号传导的可用性， 与过量类维生素A积累相关的细胞毒性。STRA 6，唯一已知的循环系统受体 ROL结合的RBP 4在眼睛中不表达，在全身组织中不表达，以促进RBP 4的摄取。 滚。这表明在这些组织中存在额外的维生素A转运蛋白。这一目标 建议1]确定一种新的维生素A转运蛋白，视黄醇结合蛋白4的生理作用 受体2（RBPR 2）促进全身摄取的饮食ROL结合RBP 4的视觉，和2]调查 如果这种眼相关ROL转运蛋白的调节可以限制毒性类维生素A所需的底物可用性， 生物合成，从而改善患有遗传性视网膜变性疾病的患者的视力。远景目标 目的是鉴定视网膜健康中RBPR 2与RBP 4结合和ROL转运的生理机制， 疾病状态。中心假设是RBPR 2在缺乏RBP 4-ROL的组织中对RBP 4-ROL具有高亲和力结合。 它的生理功能对于确保和调节膳食维生素A的摄取和递送至关重要 在视觉上的支持。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中隔离到全身组织中， 缺乏STRA 6的外周组织，用于最终分布到眼睛以获得视觉。核心假设是 通过追求三个具体目标进行测试，具体目标1：确定RBPR 2的功能， 维生素A转运;具体目标2：确定RBPR 2对系统性RBP 4-ROL的生理作用 具体目标3：确定Rbpr 2活性的调节是否减弱遗传性视网膜色素变性， 退化性疾病我们将采用结构分析、 生物化学，细胞生物学，生理学和新的动物模型，旨在探索在体内的要求， RBPR 2用于ROL转运以促进感光细胞健康、视力和视网膜疾病。拟议的研究是 意义重大，因为它将首次确定影响循环RBP 4-ROL摄取的机制， 储存和运输到眼睛，并探索旨在调节这种眼睛相关ROL的策略， 用于改善患有遗传性视网膜疾病的人的视力的转运蛋白。第二次世界大战的最后结果 拟议的研究将提供关于一种新型ROL转运蛋白RBPR 2的信息，这将提高对它的理解。 人类疾病状态，特别是失明，与受损的血液维生素A稳态或眼 维生素A过量，并可能产生预防和治疗的概念。