Recycling of metabolites from ingested outer segments supports visual function

从摄入的外节中回收代谢物支持视觉功能

• 批准号: 9233118
• 负责人: Kathleen Boesze-Battaglia
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233118
• 关键词: Affect; Autophagocytosis; Autophagosome; Carbon; Carnitine; Cell physiology; Cells; Citric Acid Cycle; Coupling; Darkness; Data; Energy-Generating Resources; Enzymes; Epithelial; Fatty Acids; Glucose; Goals; Health; Homeostasis; In Vitro; Inflammasome; Ketone Bodies; Ketones; Knock-out; Knockout Mice; Light; Link; Lipids; Metabolic; Metabolism; Mitochondria; Muller' s cell; Neural Retina; Neuroglia; Oxides; Palmitates; Pathway interactions; Phagocytes; Phagocytosis; Phagosomes; Phenotype; Phospholipids; Photoreceptors; Physiological; Play; Process; Production; Proteins; Publishing; Recycling; Regulation; Retina; Retinal; Retinal Degeneration; Retinal Pigments; Role; Source; Structure of retinal pigment epithelium; Testing; Vascular blood supply; Vision; aerobic glycolysis; age related; autocrine; base; beta-Hydroxybutyrate; fatty acid metabolism; fatty acid oxidation; genetic regulatory protein; in vivo Model; insight; ketogenesis; mitochondrial dysfunction; novel; oxidation; peroxisome; prevent; public health relevance

 DESCRIPTION (provided by applicant): Normal visual function is dependent on the intimate structural and functional interactions amongst RPE-Müller-photoreceptor cells. Photoreceptor (PR) cells have a high rate of metabolism that is supported by glucose from the choroidal blood supply and lactate produced by Müller glial cell through aerobic glycolysis. An often overlooked source of metabolic substrates is the daily meal of photoreceptor outer segments (OS) taken up by the RPE. On a daily basis, photoreceptors cells shed approximately 10% of their OSs shortly after light onset; these are then phagocytosed and degraded by the overlaying RPE. Utilization of this fatty acid and protein rich OS for fatty acid oxidation and ketogenesis by the RPE has not previously been investigated. Thus, our long term goal is to determine to what extent RPE cells utilize OSs for not only their own energy needs but also in supporting normal visual function. Our studies will establish a fundamental understanding of the metabolic fate of OS lipids as substrates for mitochondrial and peroxisomal (Prx) β-oxidation. In these studies we will test the hypothesis that ingested OS lipids are used for fatty acid β-oxidation and ketogenesis to supply metabolites to the neural retina for catabolic and anabolic processes. We further propose that these processes are regulated by autophagy. In the first Specific aim we will determine if the RPE uses lipids from shed photoreceptor outer segments (OS) for fatty acid β-oxidation (FAO) and ketogenesis. We will subsequently determine the role of BHB in maintaining RPE, photoreceptor cell and Müller cell (MC) heath and function. We will follow regulation of these processes by determining how autophagic pathways affect the utilization of OS for ketogenesis. Collectively, these studies provide a novel mechanistic link between OS degradation and fatty acid metabolism and insight into how mitochondrial dysfunction could contribute to the accumulation of lipid debris observed in age related retinal degeneration.

 描述（由申请人提供）：正常的视觉功能依赖于RPE-米勒-感光细胞之间的密切结构和功能相互作用。光感受器（PR）细胞具有高代谢率，其由来自脉络膜血液供应的葡萄糖和由Müller胶质细胞通过有氧糖酵解产生的乳酸支持。代谢底物的一个经常被忽视的来源是由RPE摄取的光感受器外节（OS）的每日膳食。每天，光感受器细胞在光照后不久脱落约10%的OS;然后这些OS被覆盖的RPE吞噬和降解。先前尚未研究RPE利用这种富含脂肪酸和蛋白质的OS进行脂肪酸氧化和生酮。因此，我们的长期目标是确定RPE细胞在多大程度上利用OS不仅用于其自身的能量需求，而且还用于支持正常的视觉功能。我们的研究将建立对OS脂质作为线粒体和过氧化物酶体（Prx）β-氧化底物的代谢命运的基本理解。在这些研究中，我们将检验以下假设：摄入的OS脂质用于脂肪酸β-氧化和酮生成，为神经视网膜提供代谢物，用于分解代谢和合成代谢过程。我们进一步提出，这些过程是由自噬调节。在第一个具体目标中，我们将确定RPE是否使用来自脱落的光感受器外节（OS）的脂质用于脂肪酸β-氧化（FAO）和生酮。我们随后将确定BHB在维持RPE，感光细胞和Müller细胞（MC）健康和功能中的作用。我们将通过确定自噬途径如何影响OS用于生酮来跟踪这些过程的调节。总的来说，这些研究提供了OS降解和脂肪酸代谢之间的新机制联系，并深入了解线粒体功能障碍如何有助于在年龄相关性视网膜变性中观察到的脂质碎片积聚。