RPE Lactate Transporters: A Role in Retinal Survival

描述(申请人提供)：正常的视觉功能依赖于RPE-üler-感光细胞之间紧密的结构和功能相互作用的维持。视网膜有很高的代谢率，这是由代谢底物的氧化和糖酵解分解代谢支持的。现在很清楚，组织中不同类型的细胞可以代谢偶联，从而一种细胞类型产生的乳酸和酮体可以被相邻的细胞利用来为氧化磷酸化提供燃料。单羧酸转运体(MCTs)在星形胶质细胞和神经元之间以及间质成纤维细胞和癌细胞之间的代谢物的穿梭中起着关键作用。在外视网膜，我们认为RPE-Müler-光感受器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的MCT阵列促进的。与这一假设一致的是对CD147(BSG)缺失小鼠的研究，其中MCT1、MCT3和MCT4表达的缺失以及视网膜外功能和存活率的严重下降都可能与MCT表达缺失导致的能量代谢变化有关。为了确定MCT1、MCT4和葡萄糖代谢对维持光感受器细胞的功能活性和存活的特殊贡献，我们提出了以下特定目标：1.验证Müller细胞糖酵解代谢对光感受器细胞至关重要的假说 功能和存活；2.检验葡萄糖和乳酸都是支持感光细胞健康和存活所必需的假说；3.检验RPE中的MCT支持RPE和外视网膜之间的代谢偶联和营养物质循环的假说，这对正常的视觉功能非常重要。这项研究将使用新的动物模型来系统地确定Glut1和MCTs的作用，并将为外部视网膜的代谢偶联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在致盲疾病的病理生理中的作用机制奠定基础。

DESCRIPTION (provided by applicant): Normal visual function is dependent on maintenance of the close structural and functional interactions between the RPE-üller-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.