Metabolism of Lactate in the Outer Retina

描述(由申请人提供)： 视网膜的能量需求是人体中最高的。葡萄糖被代谢以满足这一需求，但并不被认为是视网膜神经元使用的主要底物。相反，来自神经胶质细胞的乳酸被认为是一种重要的能量来源。这一假说得到了视网膜中单羧酸转运体(MCTs)的独特模式的支持，其中MCT1由光感受器表达，MCT4特异地表达于Muller胶质细胞，Muller胶质细胞是以多种方式支持光感受器功能的主要神经胶质细胞。缺乏CD147的小鼠的严重视网膜表型也支持TE假说，CD147是正常表达MCT1所必需的辅助蛋白。我们将使用MCT1、MCT4和CD147的全身性和条件性小鼠模型来确定乳酸的作用以及MCTs在支持视网膜能量代谢方面的作用。该项目由两个具体目标组成。目的1将利用视觉电生理学、解剖学和生物化学方法对新建立的MCT4突变小鼠的视网膜进行表征。AIM 2将把同样的技术应用于MCT1突变小鼠。首先，我们将比较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，我们将通过细胞特异性删除CD147来消除视杆细胞和/或视锥细胞感光细胞中MCT1的表达。在这个项目完成后，我们将了解MCT1和MCT4在支持视杆细胞和视锥细胞的新陈代谢和存活中所起的作用。我们将知道穆勒胶质细胞是否是视网膜乳酸的重要来源，以及乳酸是否是视杆细胞和/或视锥感光细胞新陈代谢的重要能源。这项研究将对视网膜外层代谢提供重要的见解，并将为理解视网膜外层疾病提供一个框架。

DESCRIPTION (provided by applicant): 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 Muller glial cells, the primary glial cell that supports photoreceptor function in multiple ways. Te 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 Muller 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.