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体内最高的。将葡萄糖代谢以满足这一需求，但并不是视网膜神经元使用的主要底物。取而代之的是，源自神经胶质细胞的乳酸被认为是重要的能源。该假设得到了视网膜中单羧酸酯转运蛋白（MCT）的独特模式的支持，其中MCT1由光感受器表达，MCT4表达是特定于Muller Glial细胞，Muller Glial细胞是支持光感受器功能的主要胶质细胞。 TE假设也得到缺乏CD147的小鼠的严重视网膜表型的支持，这是正常MCT1表达所需的辅助蛋白。我们将对MCT1，MCT4和CD147使用全身和条件小鼠模型来定义乳酸的作用及其通过MCT进行的运输在支持视网膜能量代谢方面。该项目由两个具体目标组成。 AIM 1将使用视觉电生理，解剖学和生化方法来表征新建立的MCT4突变小鼠的视网膜。 AIM 2将将这些相同的技术应用于MCT1突变小鼠。首先，我们将比较MCT1 +/-杂合子的视网膜表型与野生型同窝材料的视网膜表型。由于MCT1敲除无法生存，因此我们将通过CD147的细胞特异性缺失消除杆和/或锥形感受器中的MCT1表达。该项目完成后，我们将了解MCT1和MCT4在支持杆和锥形感受器的代谢和存活中所起的作用。我们将知道Muller Glial细胞是否是视网膜乳酸的重要来源，以及乳酸是否是杆和/或锥形感受器代谢的重要能量来源。这项研究将为外部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。