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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由适用提供）：正常的视觉函数取决于RPE-Müller-Photoreceptor细胞之间的紧密结构和功能相互作用。光感受器（PR）细胞具有高代谢率，这是由脉络膜血液供应和米尔神经胶质细胞通过有氧糖糖溶解产生的葡萄糖和乳酸支持的。代谢底物的一种通常被忽略的来源是RPE吸收的光感受器外部细分（OS）的每日餐。每天，光感受器细胞在光发作后不久就会散发出其OSS的10％。然后将这些吞噬并通过覆盖RPE降解。以前尚未研究这种脂肪酸和富含蛋白质的OS用于脂肪酸氧化和生酮发生的RPE。这是我们的长期目标是确定RPE单元格不仅可以为其自身的能量需求，而且还支持正常的视觉功能，从而确定RPE单元格的程度。我们的研究将建立对OS脂质代谢命运作为线粒体和过氧化物体（PRX）β-氧化的底物的基本理解。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-氧化和生酮发生，以向神经视网膜提供代谢物以进行分解代谢和合成代谢过程。我们进一步建议这些过程受自噬调节。在第一个特定目的中，我们将确定RPE是否使用Shed感光细胞外部段（OS）的脂质进行脂肪酸β-氧化（FAO）和酮症发生。随后，我们将确定BHB在维持RPE，感光细胞和Müller细胞（MC）热和功能中的作用。我们将通过确定自噬途径如何影响OS用于生酮发生的利用来遵循这些过程的调节。总的来说，这些研究提供了OS降解与脂肪酸代谢之间的新机械联系，并深入了解了线粒体功能障碍如何有助于与年龄相关的残余变性中观察到的脂质碎片的积累。