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Spatially resolved measurements of retinal metabolism

视网膜代谢的空间分辨测量

基本信息

批准号：
9906901
负责人：
ROBERT A. LINSENMEIER
金额：
$ 31.6万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906901
关键词：
Acids Address Aerobic Age related macular degeneration Anaerobic Bacteria Animal Model Automobile Driving Blood Circulation Blood flow Carbon Dioxide Cell Respiration Cells Consumption Coupling Data Dependence Diabetic Retinopathy Diffusion Disease Electroretinography Energy Metabolism Ensure Equilibrium Evaluation Event Frequencies Functional disorder Future Generations Glucose Glycolysis Health Hypoxia In Vitro Knowledge Lead Light Lighting Location Measurement Measures Metabolic Metabolic Pathway Metabolism Methods Microelectrodes Modeling Monitor Muller&apos s cell Mus Muscle Neural Retina Neuraxis Neurons Neurophysiology - biologic function Oxygen Oxygen Consumption Oxygen saturation measurement Pharmacology Photoreceptors Physiological Preparation Process Production Protons Pyruvate Rattus Research Resolution Retina Retinal Artery Occlusion Retinopathy of Prematurity Role Secondary to Side Stream Stress Techniques Testing Time Tissues Transgenic Model Up-Regulation Vascular Endothelial Growth Factors Vascular blood supply Work anaerobic glycolysis extracellular in vivo mathematical model metabolic poison metabolic rate neovascular neurovascular coupling novel strategies response vein occlusion wasting

项目摘要

Abstract Understanding retinal metabolism in detail is fundamental to knowing how the retina withstands, compensates for, or suffers from the stresses imposed by systemic changes and disease. This application takes a new approach to understanding glycolytic and oxidative metabolism of the mammalian retina, by recording spatial profiles of oxygen and pH in the isolated rat and mouse retina with microelectrodes, using mathematical models of diffusion to extract information about rates of substrate utilization and waste generation, and employing pharmacology to isolate different processes. This strategy is complimentary to previous in vivo and in vitro approaches, but allows a separation of metabolic events in the inner and outer retina, which has rarely been possible, and cannot be done with measurements of whole tissue metabolism. Microelectrode approaches simultaneously allow recording of transretinal and intraretinal electroretinograms to monitor retinal function. There are three aims. 1) Depth profiles of oxygen will be recorded in order to determine quantitatively how the metabolism of the isolated retina compares to that in vivo, and how the inner and outer retina differ metabolically. Photoreceptors are known to perform high rates of (anaerobic) glycolysis, but the balance between oxidative and glycolytic energy production is not known in the inner retina, and whether this changes depending on glucose supply. Retinal blood flow increases in response to flickering light (neurovascular coupling), but the size of the metabolic change in the inner retina that drives this is unknown, and will be measured here. 2) By recording depth profiles of pH in the isolated retina, the production of acidic waste will be quantified. Glycolysis and oxidative metabolism are very different in acid production. To identify the components of acid production, hypoxia and metabolic poisons that suppress either glycolysis or oxidative metabolism will be used. 3) In some tissues there is evidence that glycolysis and oxidative metabolism are compartmentalized, with a transfer of lactate and/or pyruvate from glycolytically active cells to ones that depend more on oxidative metabolism. This concept has led to the idea that the retina uses a similar strategy, with lactate being produced in Muller cells and shuttled to neurons. The relatively recent availability of selective blockers of monocarboxylate transport, provides an opportunity to evaluate the importance of such transfer quantitatively in both the inner and outer retina. All the information to be gained is fundamental to understanding how the retina changes in disease, and what the capabilities of the inner and outer retina are for oxidative and glycolytic metabolism under different conditions.

抽象的详细了解视网膜代谢对于了解视网膜如何承受和补偿至关重要因或遭受系统变化和疾病带来的压力。该应用程序采用了新的通过记录空间来了解哺乳动物视网膜的糖酵解和氧化代谢的方法使用微电极，使用数学方法绘制离体大鼠和小鼠视网膜中的氧气和 pH 值扩散模型以提取有关底物利用率和废物产生率的信息，以及利用药理学来分离不同的过程。该策略是对之前的体内和体外方法，但允许将内视网膜和外视网膜的代谢事件分开，这很少见是可能的，但无法通过整个组织代谢的测量来完成。微电极方法同时允许记录经视网膜和视网膜内视网膜电图以监测视网膜功能。有三个目标。 1) 记录氧气的深度剖面，以便定量确定离体视网膜的新陈代谢与体内相比如何，以及内视网膜和外视网膜有何不同新陈代谢上。众所周知，光感受器能够进行高速率的（无氧）糖酵解，但平衡视网膜内层氧化和糖酵解能量产生之间的关系尚不清楚，也不知道这是否会改变取决于葡萄糖的供应。视网膜血流量因闪烁光的反应而增加（神经血管耦合），但驱动此的内视网膜代谢变化的大小是未知的，并且将是在这里测量。 2) 通过记录离体视网膜中 pH 值的深度分布，酸性废物的产生将量化。糖酵解和氧化代谢在产酸方面有很大不同。为了识别产酸、缺氧和抑制糖酵解或氧化的代谢毒物的成分新陈代谢会被利用。 3) 在某些组织中，有证据表明糖酵解和氧化代谢是区室化，乳酸和/或丙酮酸从糖酵解活性细胞转移到糖酵解活性细胞更多地依赖于氧化代谢。这个概念导致了视网膜使用类似策略的想法，米勒细胞中产生乳酸并穿梭至神经元。相对较新的可用性单羧酸转运的选择性阻断剂提供了评估此类重要性的机会在内视网膜和外视网膜中定量传输。所获得的所有信息对于了解视网膜在疾病中如何变化，以及内视网膜和外视网膜的功能有何用途不同条件下的氧化代谢和糖酵解代谢。