RPE LACTATE TRANSPORTERS--A ROLE IN RETINAL SURVIVAL

RPE 乳酸转运蛋白——在视网膜存活中的作用

• 批准号: 6384725
• 负责人: NANCY Jean PHILP
• 金额: $ 33.19万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6384725
• 关键词: apical membrane; basolateral membrane; biological fluid transport; carboxylate; chemical structure function; electroporation; electroretinography; enzyme activity; fatty acid transport; gene expression; gene targeting; genetically modified animals; immunocytochemistry; laboratory mouse; laboratory rabbit; lactates; light microscopy; macular degeneration; molecular cloning; northern blottings; nucleic acid sequence; polymerase chain reaction; retina degeneration; retinal pigment epithelium; visual photoreceptor; water channel

The retinal pigment epithelium (RPE) is the gatekeeper of the outer retina. It forms the outer blood-retinal barrier and regulates the movements of metabolites, ions, and fluid between the choroidal blood vessels and the neural retina. Specific proteins regulate the barrier and transport properties of the RPE. Since the disturbance of either the barrier or the carrier functions could have deleterious effects on the retina, it is important to identify and characterize the proteins that mediate these functions. The retina uses aerobic glycolysis and produces substantial quantities of lactate, both in the light and in the dark. Excess lactate is transported out of the subretinal space (SRS) to the choroid by the RPE. The movement of lactate across plasma membranes is mediated by proton- coupled monocarboxylate transporters (MCTs). The RPE cells express two monocarboxylate transporters, MCT1 and MCT3 that are polarized to the apical and the basolateral membranes of the RPE, respectively. While MCT1 is expressed in many tissues MCT3 has been detected only in RPE cells. Regulating lactate levels in the SRS is essential for maintaining the pH, osmolarity, and volume in the matrix surrounding photoreceptor cells. It is our hypothesis that it is the coordinated activity of the MCTs in the apical and basolateral membrane of the RPE that regulates the movement of lactate and water out of the subretinal space. It is likely that changes in MCT3 expression or activity would over time compromise the health and function of photoreceptor cells. The goals of these studies are to characterize the temporal and spatial expression of MCT1 and MCT3 in developing mouse RPE. We will determine whether the expression of MCT3 is altered in animals with retinal degenerations. The results of these studies will provide new and important information regarding the role of RPE specific transporters in regulating lactate and fluid movement out of the subretinal space. These studies should indicate whether defects in the MCT3 gene could be linked to RPE pathologies such as macular degeneration.

视网膜色素上皮 (RPE) 是外层视网膜的看门人 视网膜。 它形成外层血视网膜屏障并调节 代谢物、离子和液体在脉络膜血之间的运动 血管和神经视网膜。 特定蛋白质调节屏障 和 RPE 的传输特性。 由于任一方的干扰 屏障或载体功能可能会对 视网膜，识别和表征蛋白质非常重要 介导这些功能。 视网膜利用有氧糖酵解并产生大量的糖酵解 乳酸，无论是在光亮还是在黑暗中。 过量的乳酸是 通过 RPE 从视网膜下腔 (SRS) 转运至脉络膜。 乳酸穿过质膜的运动是由质子介导的 耦合单羧酸转运蛋白（MCT）。 RPE 细胞表达两种 单羧酸转运蛋白 MCT1 和 MCT3 极化至 分别是 RPE 的顶膜和基底外侧膜。 尽管 MCT1 在许多组织中表达 MCT3 仅在 RPE 中检测到 细胞。 调节 SRS 中的乳酸水平对于 维持基质周围的 pH 值、渗透压和体积 感光细胞。 我们的假设是协调 RPE 顶膜和基底外侧膜中 MCT 的活性 调节乳酸和水从视网膜下的运动 空间。 MCT3 表达或活性的变化可能会 随着时间的推移，会损害感光细胞的健康和功能。 这些研究的目标是描述时间和空间的特征 MCT1 和 MCT3 在发育中的小鼠 RPE 中的表达。 我们将确定 视网膜视网膜病变动物中 MCT3 的表达是否发生改变 退化。 这些研究的结果将提供新的和 有关 RPE 特定转运蛋白作用的重要信息 调节乳酸和液体从视网膜下腔的运动。 这些研究应该表明 MCT3 基因的缺陷是否可能与 与黄斑变性等 RPE 病理有关。