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: 10601117
• 负责人: Kathleen Boesze-Battaglia
• 金额: $ 43.12万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601117
• 关键词: Acetyl Coenzyme A; 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; Modeling; Mus; NADH; Neural Retina; Neuroglia; Oxidative Phosphorylation; Oxygen; Pathway interactions; Phagocytes; Photoreceptors; Play; Production; Protons; Pyruvate; Recycling; Retina; Retinal Photoreceptors; Rod; Role; 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; postmitotic; 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.

视觉功能取决于视网膜和视网膜之间的结构、功能和代谢的密切相互作用。 视网膜色素上皮（RPE）和神经视网膜。光感受器（PR）细胞具有高的 葡萄糖和氧气的持续供应所支持的新陈代谢率 脉络膜脉管系统RPE形成外血视网膜屏障并将葡萄糖转运至视网膜。 通过顶膜和基底外侧膜中的GLUT1转运蛋白的外视网膜。的RPE 通过氧化由有氧糖酵解产生的乳酸， 外视网膜和脂肪酸来源于摄取的光感受器外节（OS）。因此，在本发明中， 我们假设RPE作为视网膜代谢稳定性的守门人， 生物能量学专业，增强视网膜燃料可用性和支持感光细胞 功能在这个角色中，至关重要的是在整个生命周期内保持RPE功能，特别是考虑到 这些细胞是有丝分裂后的脂肪酸和乳酸盐的RPE氧化维持其 由于氧化代谢的变化导致RPE去分化，因此分化和PR起作用。 我们假设，脂肪酸氧化（FAO）的有益效果与 生酮作用将（1）为RPE提供能量并防止脂肪变性（2）使线粒体再氧化 NADH以促进乳酸盐利用，（3）减少RPE对葡萄糖的依赖，从而使其免于用于 （4）通过βHB的酮解作用为PR提供燃料。而且我们 假设乳酸盐不仅是RPE中能量产生燃料，而且是乳酸盐的副产物 氧化调节溶酶体pH和基因转录。我们的长期目标是确定 控制视网膜外层代谢共生的途径，以维持正常视力超过一个月。 辈子这些假设将在以下具体目标中进行检验。具体目标1：确定 长链脂肪酸的氧化是否是维持代谢稳态所必需的， RPE的分化。具体目标2：确定如何协调促进平等股的活动 酮生成和PR酮分解支持视觉功能。具体目标3：确定 通过视网膜外层PR和M. L. ller胶质细胞有氧糖酵解产生的乳酸支持RPE 代谢和分化以及维持溶酶体pH。这些研究 证明了外太空中代谢特化细胞之间的共生关系， 视网膜。对RPE、PR或M细胞的损伤可引起非自主性变化， 对整个系统产生负面影响并导致视力丧失。

项目成果

AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration.

• DOI: 10.1038/s42003-021-02872-x
• 发表时间: 2021-12-09
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Miyagishima KJ;Sharma R;Nimmagadda M;Clore-Gronenborn K;Qureshy Z;Ortolan D;Bose D;Farnoodian M;Zhang C;Fausey A;Sergeev YV;Abu-Asab M;Jun B;Do KV;Kautzman Guerin MA;Calandria J;George A;Guan B;Wan Q;Sharp RC;Cukras C;Sieving PA;Hufnagel RB;Bazan NG;Boesze-Battaglia K;Miller S;Bharti K
• 通讯作者: Bharti K