Metabolism of Lactate in the Outer Retina

外视网膜中乳酸的代谢

基本信息

批准号：
8974361
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
项目类别：
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

项目摘要

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.

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种需求，但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。这一假设得到了视网膜中单羧酸转运蛋白 (MCT) 独特模式的支持，其中 MCT1 由光感受器表达，MCT4 表达是 Muller 胶质细胞特有的，而 Muller 胶质细胞是以多种方式支持光感受器功能的初级胶质细胞。缺乏 CD147 的小鼠的严重视网膜表型也支持了这一假设，CD147 是正常 MCT1 表达所需的辅助蛋白。我们将使用 MCT1、MCT4 和 CD147 的系统性和条件性小鼠模型来定义乳酸及其通过 MCT 的转运在支持视网膜能量代谢中的作用。该项目由两个具体目标组成。目标 1 将使用视觉电生理学、解剖学和生化方法来表征新建立的 Mct4 突变小鼠的视网膜。目标 2 将把这些相同的技术应用于 Mct1 突变小鼠。首先，我们将比较 Mct1+/-杂合子与野生型同窝小鼠的视网膜表型。由于 Mct1 敲除无法存活，我们将通过细胞特异性删除 CD147 来消除视杆细胞和/或视锥细胞光感受器中的 Mct1 表达。该项目完成后，我们将了解 MCT1 和 MCT4 在支持视杆细胞和视锥细胞光感受器的新陈代谢和存活中所发挥的作用。我们将了解米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/或视锥细胞光感受器代谢的重要能量来源。这项研究将为外视网膜代谢提供重要的见解，并将为理解外视网膜疾病提供一个框架。