Proline metabolism in retinal health

脯氨酸代谢与视网膜健康

• 批准号: 10178276
• 负责人: Jianhai Du
• 金额: $ 38万
• 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/10178276
• 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.

项目摘要/摘要 与年龄相关的黄斑变性（AMD）是老年失明的主要原因。一个共同的功能 在AMD中是视网膜色素上皮（RPE）的早期损害，这是感光体之间细胞的单层 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运输 证据表明，RPE中的新陈代谢改变是AMD的基本机制。长期 该项目的目标是确定RPE的关键代谢特征及其在AMD中扮演的角色。 我们最近发现，除葡萄糖外，RPE优先使用氨基酸脯氨酸来促进其代谢。 人类脯氨酸代谢中酶的突变可能导致脉络化萎缩或视网膜 退化。观察到脯氨酸转运蛋白高度富集在RPE中，而不是在感光体中， 进一步支持我们的发现。脯氨酸转运蛋白是与AMD相关的新型风险基因。在我们的初步中 数据，我们表明，脯氨酸转运蛋白块的敲除可产生利用并损害视觉功能。 该提案的目的是研究RPE中的脯氨酸代谢及其在视网膜变性中的作用。我们 计划使用高级示踪剂严格研究脯氨酸在健康和患病的RPE中的作用 方法论，质谱，体内输注，实时成像和脯氨酸转运蛋白敲除小鼠 型号。 这项研究的结果将是为RPE代谢建立一个概念框架 RPE如何使用营养与外​​视网膜保持代谢稳态。这个新知识将 为理解AMD的机制提供了基础，并为开发新的基础奠定了基础 治疗。