Respiration in vivo in the Retina and RPE

视网膜和 RPE 中的体内呼吸

• 批准号: 10390379
• 负责人: JAMES Bryant HURLEY
• 金额: $ 21.4万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390379
• 关键词: Animals; Back; Biochemical; Blood; Blood flow; Carbon; Catheters; Choroid; Consumption; Data; Disease; Disease Resistance; Electron Transport; Electrons; Energy Metabolism; Environment; Eye; Fumarates; Glucose; Glycolysis; Grant; Hypoxia; Infusion procedures; Label; Light; Malates; Measures; Mediating; Metabolic; Metabolic Pathway; Methods; Mitochondria; Modeling; Mus; Nutrient; Nutritional; Oxidants; Oxides; Oxygen; Oxygen Consumption; Pathway interactions; Photoreceptors; Physiological; Protocols documentation; Publishing; Reporting; Resistance; Respiration; Retina; Retinal Degeneration; Retinal Pigments; Stress; Structure of jugular vein; Structure of retinal pigment epithelium; Succinates; Testing; Therapeutic; Time; Tissues; Water; base; circadian; clinically significant; experimental study; follow-up; in vivo; mouse model; oxidative damage; photoreceptor degeneration; respiratory

Project Summary/Abstract Metabolic fuels from the choroidal blood must pass through the retinal pigment epithelium (RPE) to reach photoreceptors in the retina. The retina and RPE have unique specialized metabolic features that facilitate this flow of nutrients. In previous studies we showed that the RPE minimizes glycolysis so that more glucose can reach the retina. More recently we showed that the retina, which is hypoxic in the eye of a living animal, transfers electrons from mitochondrial respiration to fumarate to make succinate instead of transferring the electrons to oxygen to make water. We also showed that succinate made and released by the retina can fuel oxygen consumption by the RPE. We have proposed a model for energy metabolism in the vertebrate eye in which succinate transfers reducing power from the hypoxic retina to the oxygen rich RPE. After succinate is oxidized by RPE cells, its carbons can be recycled from the RPE back to the retina to accept more electrons and transfer them to oxygen in the RPE. We reported recently several lines of evidence that support this model for a succinate-mediated metabolic cycle in the eye. The evidence so far is based on ex vivo analyses of healthy, functioning retina and RPE/choroid living tissues. However, it also is important to establish to what extent this metabolic cycle occurs in vivo, i.e. in the eyes of living animals. Recently we established an experimental protocol in which we infuse 13C labeled metabolic fuels including succinate and malate through catheters into the jugular veins of mice. We then measure the time course and steady state levels of incorporation of 13C into metabolites in the retina and RPE/choroid. In Aim 1 of this proposal we will confirm our initial findings that the succinate cycle occurs in vivo and we will optimize the infusion protocols. In Aim 2 we will use in vivo infusion to show how circadian and diurnal cycles influence metabolic flux between the retina and RPE. In Aim 3 we will explore strategies to exploit the succinate cycle to slow degeneration of photoreceptors in mouse models of retinal degeneration.

项目总结/文摘