Recycling of Metabolites from Ingested Outer Segments Supports Visual Function

从摄入的外段回收代谢物支持视觉功能

• 批准号: 10393554
• 负责人: Kathleen Boesze-Battaglia
• 金额: $ 41.83万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393554
• 关键词: Amino Acids; Bioenergetics; Blindness; Blood-Retinal Barrier; Carnitine Palmitoyltransferase I; Cell Respiration; Cells; Disease; Energy-Generating Resources; Enzymes; Fatty Acids; Feedback; Gatekeeping; Gene Expression; Generations; Genetic Transcription; Glucose; Goals; Histone Acetylation; Homeostasis; Inflammation; Ingestion; Ketone Bodies; Lead; Lipids; Liver; Maintenance; Metabolic; Metabolic Control; Metabolism; Mitochondria; Mitotic; Modeling; Mus; NADH; Neural Retina; Neuroglia; Oxidative Phosphorylation; Oxides; Oxygen; Pathway interactions; Phagocytes; Photoreceptors; Play; Production; Protons; Pyruvate; Recycling; Retina; Retinal Photoreceptors; Rod; Role; Route; SLC2A1 gene; Structure of retinal pigment epithelium; Symbiosis; System; Testing; Time; Transgenic Mice; Vision; aerobic glycolysis; apical membrane; basolateral membrane; beta-Hydroxybutyrate; fatty acid oxidation; glucose transport; ketogenesis; long chain fatty acid; mitochondrial dysfunction; mouse model; negative affect; oxidation; prevent; response; retinal damage; synergism; Amino Acids; Bioenergetics; Blindness; Blood-Retinal Barrier; Carnitine Palmitoyltransferase I; Cell Respiration; Cells; Disease; Energy-Generating Resources; Enzymes; Fatty Acids; Feedback; Gatekeeping; Gene Expression; Generations; Genetic Transcription; Glucose; Goals; Histone Acetylation; Homeostasis; Inflammation; Ingestion; Ketone Bodies; Lead; Lipids; Liver; Maintenance; Metabolic; Metabolic Control; Metabolism; Mitochondria; Mitotic; Modeling; Mus; NADH; Neural Retina; Neuroglia; Oxidative Phosphorylation; Oxides; Oxygen; Pathway interactions; Phagocytes; Photoreceptors; Play; Production; Protons; Pyruvate; Recycling; Retina; Retinal Photoreceptors; Rod; Role; Route; SLC2A1 gene; Structure of retinal pigment epithelium; Symbiosis; System; Testing; Time; Transgenic Mice; Vision; aerobic glycolysis; apical membrane; basolateral membrane; beta-Hydroxybutyrate; fatty acid oxidation; glucose transport; ketogenesis; long chain fatty acid; mitochondrial dysfunction; mouse model; negative affect; oxidation; prevent; response; retinal damage; synergism

Visual function depends on the intimate structural, functional and metabolic interactions between the retinal pigment epithelium (RPE) and the neural retina. Photoreceptor (PR) cells have a high rate of metabolism that is supported through a continuous supply of glucose and oxygen from the choroidal vasculature. The RPE forms the outer blood retinal barrier and transports glucose to the outer retina via GLUT1 transporters in both the apical and basolateral membranes. The RPE spares glucose for the outer retina by oxidizing lactate generated through aerobic glycolysis in the outer retina and fatty acids derived from ingested photoreceptor outer segments (OS). Thus, we hypothesize that the RPE serves as the gatekeeper of retinal metabolic stability through bioenergetics specializations that enhance retinal fuel availability and support photoreceptor function. In this role, it is critical that RPE function be maintained over a lifetime, especially given that these cells are post-mitotic. RPE oxidation of fatty acids and lactate maintains its differentiation and PR function as changes in oxidative metabolism lead to RPE dedifferentiation. We hypothesize that the beneficial effects of fatty acid oxidation (FAO) working in synergy with ketogenesis will (1) provide energy for the RPE and prevent steatosis (2) reoxidize mitochondrial NADH to facilitate lactate utilization, (3) decrease RPE reliance on glucose thereby sparing it for the neural retina and (4) provide fuel for PR through ketolysis of βHB. Furthermore, we hypothesize that lactate is not only a fuel for energy production in RPE, but by-products of lactate oxidation regulate lysosomal pH and gene transcription. Our long-term goal is to identify the pathways that control metabolic symbiosis in the outer retina to sustain normal vision over a lifetime. The hypotheses will be tested in the following specific aims. Specific aim 1: To determine whether oxidation of long chain fatty acids is necessary to maintain metabolic homeostasis and differentiation of the RPE. Specific Aim 2: To determine how the coordinated activities of RPE ketogenesis and PR ketolysis support visual function. Specific Aim 3: To determine whether lactate produced through aerobic glycolysis in PR and Mϋller glia in the outer retina supports RPE metabolism and differentiation as well as maintenance of lysosomal pH. Collectively these studies demonstrate the symbiotic relationship among the metabolically specialized cells in the outer retina. Damage to the RPE, PR or Mϋller cells can cause non-autonomous changes that negatively affect the entire system and lead to vision loss.

视觉功能取决于牢固的结构，功能和代谢相互作用 视网膜色素上皮（RPE）和神经视网膜。感光细胞（PR）细胞具有较高的 通过连续葡萄糖和氧气供应支持的代谢率 脉络膜脉管系统。 RPE形成外血残留屏障，并将葡萄糖运输到 顶端和基底外侧膜中的GLUT1转运蛋白外视网膜外。 RPE 通过在有氧糖酵解中产生的氧化鞋底，用于外部视网膜葡萄糖。 源自摄入的光感受器外部片段（OS）的视网膜外视网膜和脂肪酸。那， 我们假设RPE通过 生物能学专业，可增强视网膜燃料可用性并支持感光器 功能。在此角色中，至关重要的是，RPE功能在一生中保持 这些细胞是有丝分裂的。脂肪酸的RPE氧化和裂缝保持其维护 分化和PR功能作为氧化代谢的变化导致RPE去分化。 我们假设在与 生酮发生（1）将为RPE提供能量并预防脂肪变性（2）重新氧化线粒体 NADH可促进缝隙利用，（3）降低葡萄糖的RPE释放，从而使其宽大 神经视网膜和（4）通过βHb的酮解提供PR的燃料。此外，我们 假设鞋底不仅是RPE能源产生的燃料，而且是副产品 氧化调节溶酶体pH和基因转录。我们的长期目标是确定 控制外视网膜中代谢共生的途径，以维持正常视力 寿命。假设将在以下特定目的中进行检验。特定目标1：确定 长链脂肪酸的氧化是否需要维持代谢稳态和 RPE的区分。特定目标2：确定RPE的协调活动如何 生酮发生和PR酮解析支持视觉功能。特定目标3：确定是否 通过在视网膜外的PR和mϋlllerGlia中通过有氧糖酵解产生的乳酸支持RPE 代谢和分化以及溶酶体pH的维持。集体这些研究 证明外部代谢专业细胞之间的共生关系 视网膜。损害RPE，PR或mϋlller细胞可能会引起非自主变化， 负面影响整个系统并导致视力丧失。