Proline metabolism in retinal health

项目摘要/摘要 老年性黄斑变性(AMD)是老年人致盲的主要原因。一个共同的特征 AMD是视网膜色素上皮(RPE)的早期损害，RPE是光感受器之间的单层细胞 脉络膜。RPE控制着从脉络膜供血到外视网膜和多条管路的营养物质运输 大量证据表明，RPE中代谢的改变是AMD的潜在机制。长期的 该项目的目标是确定RPE的关键代谢特征及其在AMD中所起的作用。 我们最近发现，除了葡萄糖，RPE还优先使用一种氨基酸--脯氨酸来为其新陈代谢提供能量。 人类脯氨酸代谢酶的突变可能导致脉络膜视网膜萎缩或视网膜 退化。观察到，Pro转运蛋白高度富含RPE，但不存在于光感受器中， 进一步支持了我们的发现。脯氨酸转运蛋白是一种新的与AMD相关的危险基因。在我们的预赛中 数据显示，Pro转运蛋白的敲除阻碍了Pro的利用，并损害了视觉功能。 本研究的目的是研究RPE中的脯氨酸代谢及其在视网膜变性中的作用。我们 计划使用高级示踪剂严格研究Pro在健康和患病RPE中的作用 方法学、质谱学、体内输注、活体成像和脯氨酸转运体基因敲除小鼠 模特们。 这项研究的结果将是建立一个RPE代谢的概念性框架，描述 RPE如何利用营养维持与外部视网膜的代谢动态平衡。这一新知识将 为认识AMD的发病机制提供基础，为开发新的AMD奠定基础 治疗。

PROJECT SUMMARY/ABSTRACT Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. A common feature in AMD is the early damage of retinal pigment epithelium (RPE), a monolayer of cells between photoreceptors and choroid. RPE controls nutrient transport from choroid blood supply to the outer retina and multiple lines of evidence show that the altered metabolism in RPE is the underlying mechanism for AMD. The long-term goal of this project is to identify key metabolic features of RPE and the roles that they play in AMD. We recently found that besides glucose, RPE preferentially uses proline, an amino acid, to fuel its metabolism. Mutations of enzymes in proline metabolism in humans could cause chorioretinal atrophy or retinal degeneration. The observation that a proline transporter is highly enriched in RPE but not in photoreceptors, further supporting our finding. The proline transporter is a novel risk gene linked to AMD. In our preliminary data, we show that knockout of the proline transporter blocks proine utilization and impairs visual function. The objective of this proposal is to study proline metabolism in RPE and its role in retinal degeneration. We plan to rigorously investigate the role of proline in healthy and diseased RPE using advanced tracer methodology, mass spectrometry, in vivo infusion, live imaging, and proline transporter knockout mouse models. The outcome of this research will be to establish a conceptual framework for RPE metabolism that describes how RPE uses nutrients to maintain metabolic homeostasis with the outer retina. This new knowledge will provide the basis for understanding the mechanisms of AMD and lay the foundation for developing new treatments.