Metabolism of Lactate in the Outer Retina

视网膜的能量需求是人体中最高的。葡萄糖是 代谢以满足这一需求，但不被认为是 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。 消息来源。这一假说得到了单羧酸转运蛋白独特模式的支持 (MCTs)，其中MCT1由光感受器表达，MCT4表达 特异于M？ller胶质细胞，是支持光感受器功能的主要神经胶质细胞 多方面的。这一假说也被严重的小鼠视网膜表型所支持 缺乏CD147，这是一种正常表达MCT1所必需的辅助蛋白。我们会 使用MCT1、MCT4和CD147的系统性和条件性小鼠模型来定义角色 支持视网膜能量代谢的MCTs对乳酸及其运输的研究。这个项目是 由两个具体目标组成。目标1将描述一个新成立的视网膜 MCT4突变小鼠，利用视觉电生理、解剖和生化 接近了。AIM 2将把同样的技术应用于MCT1突变小鼠。首先，我们会 比较MCT1/-杂合子和野生型小鼠的视网膜表型。 由于MCT1基因敲除不能存活，我们将消除MCT1在杆状病毒和/或 视锥感光细胞CD147的细胞特异性缺失。在这个项目完成后，我们 将了解MCT1和MCT4在支持新陈代谢和生存中所起的作用 杆状和锥状感光器。我们将知道M？ler神经胶质细胞是否是一个重要的 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 视锥感光细胞新陈代谢。这项研究将为外部世界提供重要的见解 视网膜新陈代谢，将为理解外周疾病提供一个框架 视网膜。

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.