Control of Photoreceptor Metabolism

描述(申请人提供)：光感受器在黑暗中的代谢需求与在光中的代谢需求有本质上的不同。在黑暗中，它们的新陈代谢就像传统神经元一样。它主要致力于为离子泵提供能量。从表面上看，它们的新陈代谢更像是癌细胞。照明降低了离子泵浦的能量需求，但它增加了 合成新膜和再生视紫红质所需的合成代谢活性。环状GMP和Ca~(2+)在光感受器响应和适应光的方式中起核心作用。改变cGMP合成或降解的遗传缺陷会导致光感受器细胞退化。我们假设GMP和Ca~(2+)影响光感受器的基本代谢活动，从而支持其功能和活性。我们正在研究光感受器的代谢需求和光感受器存活之间的关系。我们开发了评估光感受器代谢的生化分析方法，我们发现cGMP的长期积累会导致谷氨酸的大量消耗，这是一种阻止蛋白质和谷胱甘肽合成的条件。这项提议的目的之一是检验这样一种假设，即谷氨酸的枯竭是某些类型的遗传性视网膜退行性疾病的光感受器退化的原因。我们将探索营养补充剂在这些疾病状态的动物模型中阻止光感受器退化的可能性。新陈代谢和生存能力也取决于环境。在完整的视网膜中，光感受器可以在培养中存活数天，但当脱离视网膜时，它们会在几个小时内退化。这项建议的第二个目的是通过表征提高光感受器存活的小分子的代谢效应来研究解离的光感受器退化的代谢基础。我们将利用这些信息来帮助确定光感受器的基本代谢需求。

DESCRIPTION (provided by applicant): Metabolic demands of photoreceptors in darkness are qualitatively different than in light. In darkness their metabolism is like that of conventiona neurons. It is devoted mostly to supplying energy to ion pumps. In light their metabolism is more like that of cancer cells. Illumination lowers energy requirements for ion pumping but it increases the demand for anabolic activity to synthesize new membranes and regenerate rhodopsin. Cyclic GMP and Ca2+ play central roles in the way photoreceptors respond and adapt to light. Genetic deficiencies that alter the synthesis or degradation of cGMP cause degeneration of photoreceptor cells. We hypothesize that GMP and Ca2+ influence basic metabolic activities in photoreceptors that support their function and viability. We are investigating relationships between metabolic needs of photoreceptors and photoreceptor survival. We developed biochemical assays that evaluate photoreceptor metabolism and we found that chronic accumulation of cGMP causes massive depletion of glutamic acid, a condition that precludes synthesis of proteins and glutathione. One aim of this proposal is to test the hypothesis that depletion of glutamate is the reason photoreceptors degenerate in certain types of inherited retinal degenerative diseases. We will explore the possibility that nutritional supplements can block photoreceptor degeneration in animal models of these disease states. Metabolism and viability also depend on environment. Photoreceptors can survive for days in culture in an intact retina, but they degenerate within hours when dissociated from the retina. The second aim of this proposal is to investigate the metabolic basis for degeneration of dissociated photoreceptors by characterizing metabolic effects of small molecules that enhance photoreceptor survival. We will use this information to help identify fundamental metabolic requirements of photoreceptors.