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

基本信息

批准号：
10468907
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
项目类别：
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/10468907
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 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

项目摘要

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：膳食维生素 A/全反式视黄醇/ROL 在全身的分布对于维持类维生素A在周围组织中发挥作用并确保最佳视力。在人类中，膳食维生素 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)。受体介导的系统对于系统性 RBP4-ROL 的摄取、储存和运输至关重要不仅是为了确保光感受器功能的最佳眼视黄醇信号传导的可用性，而且还为了防止与过量维A酸积累相关的细胞毒性。 STRA6，唯一已知的循环受体 ROL 在眼睛中与 RBP4 结合，在全身组织中不表达，建议促进 RBP4 的摄取- 罗尔。这表明这些组织中存在额外的维生素 A 转运蛋白。本次活动的目标建议是 1] 确定新型维生素 A 转运蛋白视黄醇结合蛋白 4 的生理作用受体 2 (RBPR2) 促进膳食 ROL 结合 RBP4 的系统摄取以促进视力，2] 进行研究此类与眼睛相关的 ROL 转运蛋白的调节是否可以限制有毒类维生素A所需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。长期目标目的是确定 RBPR2 在视网膜健康中与 RBP4 结合和 ROL 转运的生理机制疾病状态。中心假设是 RBPR2 在缺乏 RBP4-ROL 的组织中具有高亲和力结合 STRA6 及其生理功能对于确保和调节膳食维生素 A 的摄取和输送至关重要给眼睛提供视觉的支持。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、运输和储存的差距缺乏STRA6的外周组织，最终分布到眼睛以实现视力。中心假设将是通过追求三个具体目标进行测试，具体目标 1：确定 RBPR2 的功能维生素A运输；具体目标 2：确定 RBPR2 对全身 RBP4-ROL 的生理作用视觉传输；具体目标 3：确定 Rbpr2 活性的调节是否会减弱遗传性视网膜退行性疾病。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需求的新型动物模型 RBPR2 用于 ROL 运输，促进光感受器健康、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 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-的策略用于改善患有遗传性视网膜疾病的人类视力的转运蛋白。近期的结果拟议的研究将提供有关新型 ROL 转运蛋白 RBPR2 的信息，这将增进理解人类疾病状态，特别是失明，与血液维生素 A 稳态或眼部受损有关维生素 A 过量，可能会产生预防和治疗的概念。