Metabolic Adaptations of Photoreceptors

描述（由申请人提供）：光感受器与大脑中的神经元不同，因为它们暴露于来自环境的电磁辐射。具有最多累积的辐射暴露的膜从光感受器外节的尖端脱落，并被外节基部新合成的膜所取代。这种类型的合成代谢活动每天发生。在这些更新时期对合成代谢的高需求让人想起癌细胞的代谢需求。癌症研究的最新发现已经确定了癌细胞的重要代谢适应，这些适应促进了癌细胞的生长。特定的生化机制将糖酵解中间产物从能量生产转移到支持生长的合成代谢途径。癌细胞进行有氧糖酵解，偏好谷氨酰胺作为其线粒体的燃料，并且它们表达一种独特形式的丙酮酸激酶PKM2，其可以通过酪氨酸磷酸化来调节。通过降低PKM2活性，癌细胞将糖酵解中间产物从能量产生转移到更多的合成代谢作用，如磷脂合成。我们已经进行了初步研究，表明光感受器使用一些与癌细胞用于增强其合成代谢活性相同类型的适应。该项目的目标是将癌症代谢研究的发现扩展到光感受器代谢的理解。我们将探讨新的假设，感光细胞调节合成代谢活动的机制类似于癌细胞。这个项目的结果将是一个框架，了解能量代谢如何影响感光功能和生存。

DESCRIPTION (provided by applicant): Photoreceptors are different from neurons in the brain because they are exposed to electromagnetic radiation from the environment. Membranes with the most accumulated exposure to radiation are shed from the tip of the photoreceptor outer segment and replaced by addition of newly synthesized membranes at the base of the outer segment. This type of anabolic activity occurs daily. The high demand for anabolic metabolism during these periods of renewal is reminiscent of the metabolic demands of cancer cells. Recent findings in cancer research have identified important metabolic adaptations of cancer cells that enhance their growth. Specific biochemical mechanisms divert glycolytic intermediates away from energy production and instead into anabolic pathways that support growth. Cancer cells carry out aerobic glycolysis, prefer glutamine as a fuel for their mitochondria and they express a unique form of pyruvate kinase, PKM2 that can be regulated by tyrosine phosphorylation. By reducing PKM2 activity cancer cells divert glycolytic intermediates away from energy production to more anabolic roles like phospholipid synthesis. We have carried out preliminary studies that suggest photoreceptors use some of the same types of adaptations that cancer cells use to enhance their anabolic activity. The goal of this project is to extend discoveries from cancer metabolism research toward an understanding of photoreceptor metabolism. We will explore the novel hypothesis that photoreceptor cells regulate anabolic activity by mechanisms similar to those used by cancer cells. The outcome of this project will be a framework with which to understand how energy metabolism influences photoreceptor function and survival.