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身体中最高的。葡萄糖 代谢，以满足这一需求，但不被认为是使用的主要底物 视网膜神经元相反，来自神经胶质细胞的乳酸被认为是一种重要的能量 源头这一假说得到了单羧酸转运蛋白的独特模式的支持 在视网膜中的MCTs，其中MCT 1由光感受器表达，MCT 4的表达由光感受器表达。 Müller神经胶质细胞特异性，Müller神经胶质细胞是支持感光细胞功能的主要神经胶质细胞， 多种方式。这一假说也得到了小鼠严重视网膜表型的支持 缺乏CD 147，这是一种正常MCT 1表达所需的辅助蛋白。我们将 使用MCT 1、MCT 4和CD 147的系统性和条件性小鼠模型来定义 乳酸及其通过MCT转运以支持视网膜能量代谢。这个项目是 包括两个具体目标。目的1将表征视网膜的一个新建立的 mct 4突变小鼠，使用视觉电生理，解剖学和生物化学 接近。Aim 2将这些相同的技术应用于Mct 1突变小鼠。首先我们将 比较Mct 1 +/-杂合子与野生型同窝仔的视网膜表型。 由于Mct 1敲除不能存活，我们将消除视杆细胞和/或视神经细胞中的Mct 1表达。 通过细胞特异性缺失CD 147的视锥光感受器。在这个项目完成后，我们 将了解MCT 1和MCT 4在支持新陈代谢和生存方面发挥的作用 视杆和视锥光感受器。我们将知道M？ller胶质细胞是否是一个重要的 视网膜乳酸盐来源以及乳酸盐是否是视杆细胞和/或视神经细胞的重要能量来源 视锥光感受器代谢这项研究将提供重要的见解， 视网膜代谢，并将提供一个框架，了解疾病的外部 视网膜。