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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：
9077816
负责人：
Kathleen Boesze-Battaglia
金额：
$ 41.1万
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/9077816
关键词：
Affect Autophagocytosis Autophagosome Carbon Carnitine Cell physiology Cells Citric Acid Cycle Coupling Data Energy-Generating Resources Enzymes Epithelial Fatty Acids Glucose Goals Health Homeostasis In Vitro Ketone Bodies Ketones Knock-out Knockout Mice Light Link Lipids Metabolic Metabolism Mitochondria Muller&apos s cell Neural Retina Neuroglia 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 meetings 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.