Metabolism of Lactate in the Outer Retina

外视网膜中乳酸的代谢

• 批准号: 8633768
• 负责人: NEAL S. PEACHEY
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633768
• 关键词: Age; Anatomy; Astrocytes; Biochemical; Brain; Catabolism; Cell Respiration; Cells; Coupling; Disease; Energy Metabolism; Energy-Generating Resources; Fibroblasts; Gene Expression; Genetic; Glucose; Health; Heterozygote; Knock-out; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; Mus; Mutant Strains Mice; Neuroglia; Neurons; Oxidative Phosphorylation; Pattern; Phenotype; Photoreceptors; Phototransduction; Play; Population; Proteins; Research; Retina; Retinal; Retinal Cone; Retinal Diseases; Retinal Photoreceptors; Role; Source; Techniques; Testing; Tissues; Vertebrate Photoreceptors; Veterans; Vision; Visual; aerobic glycolysis; cell type; extracellular; insight; mouse model; neoplastic cell; neuronal survival; public health relevance; retinal neuron; retinal rods; rho; uptake

The energy demands of the retina are some of the highest in the body. Glucose is metabolized to satisfy this demand, but is not thought to be the primary substrate used by retinal neurons. Instead, lactate derived from glial cells is thought to be an important energy source. This hypothesis is supported by the unique pattern of monocarboxylate transporters (MCTs) in the retina, in which MCT1 is expressed by photoreceptors and MCT4 expression is specific to M¿ller glial cells, the primary glial cell that supports photoreceptor function in multiple ways. The hypothesis is also supported by the severe retinal phenotype of mice lacking CD147, an accessory protein that is required for normal MCT1 expression. We will use systemic and conditional mouse models for MCT1, MCT4, and CD147 to define the role of lactate and its transport by MCTs in support of retinal energy metabolism. This project is comprised of two Specific Aims. Aim 1 will characterize the retina of a newly established Mct4 mutant mouse, using visual electrophysiological, anatomical and biochemical approaches. Aim 2 will apply these same techniques to Mct1 mutant mice. First we will compare the retinal phenotype of Mct1+/-heterozygotes with that of wild type littermates. Since the Mct1 knock-out does not survive, we will eliminate Mct1 expression in rod and/or cone photoreceptors by cell-specific deletion of CD147. At the completion of this project, we will understand the role that MCT1 and MCT4 play in supporting metabolism and survival of rod and cone photoreceptors. We will know whether M¿ller glial cells are an important source of retinal lactate and whether lactate is an important source of energy for rod and/or cone photoreceptor metabolism. This research will provide important insights into outer retinal metabolism and will provide a framework for understanding diseases of the outer retina.

视网膜的能量需求是体内最高的。 代谢以满足这种需求，但不被认为是 相反，来自神经胶质细胞的乳酸被认为是一种重要的能量。 这一假设得到了单羧酸转运蛋白独特模式的支持。 视网膜中的MCT（MCT），其中MCT1由光感受器表达，MC​​T4表达为 特定于 M¿小胶质细胞，支持光感受器功能的初级胶质细胞 该假设也得到了小鼠严重视网膜表型的支持。 缺乏 CD147，这是正常 MCT1 表达所需的辅助蛋白。 使用 MCT1、MCT4 和 CD147 的系统性和条件性小鼠模型来定义其作用 该项目旨在研究乳酸及其通过 MCT 的运输，以支持视网膜能量代谢。 由两个具体目标组成，目标 1 将描述新建立的视网膜的特征。 Mct4突变小鼠，利用视觉电生理学、解剖学和生物化学 目标 2 会将这些相同的技术应用于 Mct1 突变小鼠。 将 Mct1+/-杂合子的视网膜表型与野生型同窝出生的视网膜表型进行比较。 由于 Mct1 敲除无法存活，我们将消除视杆细胞中的 Mct1 表达和/或 通过细胞特异性删除 CD147 来形成视锥光感受器 在该项目完成时，我们 将了解 MCT1 和 MCT4 在支持新陈代谢和生存中发挥的作用 我们将知道 M¿填充胶质细胞是重要的 视网膜乳酸的来源以及乳酸是否是视杆细胞和/或视杆细胞的重要能量来源 这项研究将为了解视锥细胞的外部代谢提供重要的见解。 视网膜代谢，将为理解外部疾病提供一个框架 视网膜。