Proline metabolism in retinal health

脯氨酸代谢与视网膜健康

• 批准号: 10412034
• 负责人: Jianhai Du
• 金额: $ 36.86万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412034
• 关键词: Age related macular degeneration; Amino Acids; Anabolism; Atrophic; Blindness; Catabolism; Cells; Choroid; Citric Acid Cycle; Clinical; Collagen; Communication; Consumption; Data; Disease; Elderly; Electron Microscopy; Electroretinography; Enzyme-Linked Immunosorbent Assay; Enzymes; Epithelial; Fatty Acids; Foundations; Glucose; Goals; Health; Homeostasis; Human; Image; Immunohistochemistry; Impairment; In Vitro; Infusion procedures; Knock-out; Knockout Mice; Knowledge; Link; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methodology; Mitochondria; Modeling; Mus; Mutation; NADP; Nitrogen; Nutrient; Nutritional Requirements; Nutritional Support; Optical Coherence Tomography; Outcomes Research; Pathogenesis; Pathway interactions; Phagocytosis; Photoreceptors; Play; Production; Proline; Property; Publications; Retina; Retinal Degeneration; Retinal Diseases; Role; Structure of retinal pigment epithelium; Support Groups; Testing; Thick; Tracer; Vascular blood supply; Vision; Visual impairment; base; extracellular; genetic signature; glucose metabolism; in vivo; macula; metabolomics; meter; mitochondrial metabolism; monolayer; mouse model; novel; novel therapeutics; oxidation; proline permease; retinal damage; risk variant; sensor; tissue culture

PROJECT SUMMARY/ABSTRACT Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. A common feature in AMD is the early damage of retinal pigment epithelium (RPE), a monolayer of cells between photoreceptors and choroid. RPE controls nutrient transport from choroid blood supply to the outer retina and multiple lines of evidence show that the altered metabolism in RPE is the underlying mechanism for AMD. The long-term goal of this project is to identify key metabolic features of RPE and the roles that they play in AMD. We recently found that besides glucose, RPE preferentially uses proline, an amino acid, to fuel its metabolism. Mutations of enzymes in proline metabolism in humans could cause chorioretinal atrophy or retinal degeneration. The observation that a proline transporter is highly enriched in RPE but not in photoreceptors, further supporting our finding. The proline transporter is a novel risk gene linked to AMD. In our preliminary data, we show that knockout of the proline transporter blocks proine utilization and impairs visual function. The objective of this proposal is to study proline metabolism in RPE and its role in retinal degeneration. We plan to rigorously investigate the role of proline in healthy and diseased RPE using advanced tracer methodology, mass spectrometry, in vivo infusion, live imaging, and proline transporter knockout mouse models. The outcome of this research will be to establish a conceptual framework for RPE metabolism that describes how RPE uses nutrients to maintain metabolic homeostasis with the outer retina. This new knowledge will provide the basis for understanding the mechanisms of AMD and lay the foundation for developing new treatments.

项目概要/摘要 年龄相关性黄斑变性（AMD）是老年人失明的主要原因。一个共同的特点 AMD 的早期损伤是视网膜色素上皮 (RPE) 的早期损伤，RPE 是光感受器之间的单层细胞 和脉络膜。 RPE 控制从脉络​​膜血液供应到外视网膜和多条线的营养物质运输 大量证据表明 RPE 代谢的改变是 AMD 的潜在机制。长期来看 该项目的目标是确定 RPE 的关键代谢特征及其在 AMD 中发挥的作用。 我们最近发现，除了葡萄糖之外，RPE 还优先使用脯氨酸（一种氨基酸）来为其代谢提供能量。 人类脯氨酸代谢酶的突变可能导致脉络膜视网膜萎缩或视网膜萎缩 退化。观察到脯氨酸转运蛋白在 RPE 中高度富集，但在光感受器中不富集， 进一步支持我们的发现。脯氨酸转运蛋白是一种与 AMD 相关的新型风险基因。在我们的初步 数据显示，脯氨酸转运蛋白的敲除会阻碍脯氨酸的利用并损害视觉功能。 本提案的目的是研究 RPE 中的脯氨酸代谢及其在视网膜变性中的作用。我们 计划使用先进的示踪剂严格研究脯氨酸在健康和患病 RPE 中的作用 方法、质谱、体内输注、实时成像和脯氨酸转运蛋白敲除小鼠 模型。 这项研究的成果将是建立一个 RPE 代谢的概念框架，描述 RPE 如何利用营养物质来维持与外视网膜的代谢稳态。这些新知识将 为理解AMD的机制提供基础，并为开发新的药物奠定基础 治疗。