RPE Lactate Transporters: A Role in Retinal Survival

描述（由申请人提供）：正常的视觉功能依赖于RPE-米勒-感光细胞之间密切的结构和功能相互作用的维持。视网膜具有高代谢率，其由代谢底物的氧化和糖酵解催化剂支持。现在清楚的是，组织内的不同细胞类型可以B代谢偶联，由此由一种细胞类型产生的乳酸盐和酮体可以被相邻细胞利用以促进氧化磷酸化。单羧酸转运蛋白（MCT）已被证明在星形胶质细胞和神经元之间以及基质成纤维细胞和癌细胞之间的代谢物穿梭中发挥关键作用。在外层视网膜中，我们提出RPE-米勒-感光细胞之间存在代谢偶联，这是由每种细胞类型中表达的独特MCT阵列促进的。与该假设一致的是CD 147（Bsg）敲除小鼠的研究，其中MCT 1、MCT 3和MCT 4表达的丧失以及外视网膜功能和存活率的显著降低均可能与MCT表达丧失导致的能量代谢变化相关。为了确定MCT 1和MCT 4以及葡萄糖代谢对维持感光细胞的功能活性和存活的具体贡献，我们提出了以下具体目的：1.验证Müller细胞糖酵解代谢葡萄糖对感光细胞至关重要的假设 功能和生存; 2。检验葡萄糖和乳酸盐都是支持感光细胞健康和存活所必需的假设; 3.检验RPE中的MCT支持RPE和外视网膜之间的营养物质的代谢偶联和再循环对正常视觉功能很重要的假设。这项研究将使用新的动物模型来系统地确定Glut 1和MCT的作用，并将为外视网膜中的代谢耦合如何维持视觉功能提供关键的新见解。我们的发现将为理解代谢变化可能导致致盲疾病的病理生理机制奠定基础。

DESCRIPTION (provided by applicant): Normal visual function is dependent on maintenance of the close structural and functional interactions between the RPE-Müller-photoreceptor cells. The retina has a high rate of metabolism, which is supported by oxidative and glycolytic catabolism of metabolic substrates. It is now clear that different cell types within a tissue can b metabolically coupled whereby lactate and ketone bodies generated by one cell type can be utilized by an adjacent cell to fuel oxidative phosphorylation. Monocarboxylate transporters (MCTs) have been shown to play a key role in the shuttling of metabolites between astrocytes and neurons as well as between stromal fibroblast and cancer cells. In the outer retina we propose that there is metabolic coupling between RPE-Müller-photoreceptor cells that is facilitated by the unique array of MCTs expressed in each cell type. Consistent with this hypothesis are studies of the CD147 (Bsg) null mouse where loss of MCT1, MCT3 and MCT4 expression and profound decreases in outer retinal function and survival may all be linked to changes in energy metabolism due to loss of MCT expression. To determine the specific contribution of MCT1 and MCT4 and glucose metabolism to maintaining the functional activity and survival of photoreceptor cells we have proposed the following Specific Aims: 1. Test the hypothesis that glycolytic metabolism of glucose by Müller cells is critical for photoreceptor cell function and survival; 2. Test the hypothesis that both glucose and lactate are required to support photoreceptor cell health and survival; 3. Test the hypothesis that MCTs in the RPE support metabolic coupling and recycling of nutrients between the RPE and outer retina important for normal visual function. This research will use novel animal models to systematically determine the role of Glut1 and MCTs and will provide critical new insights into how metabolic coupling in the outer retina maintains visual function. Our finding will lay the groundwork for understanding mechanism through which metabolic changes could contribute to the pathophysiology of blinding diseases.