Control of Photoreceptor Metabolism

描述（由申请人提供）：光感受器在黑暗中的代谢需求与在光照下的代谢需求有质的不同。在黑暗中，它们的新陈代谢就像传统神经元一样。它主要用于为离子泵提供能量。在光中，它们的新陈代谢更像癌细胞。照明降低了离子泵送的能量需求，但它增加了 合成新膜和再生视紫红质的合成代谢活性的需求。环GMP和Ca2+在光感受器响应和适应光的方式中起着核心作用。改变cGMP合成或降解的遗传缺陷导致感光细胞变性。我们假设GMP和Ca2+影响支持其功能和生存能力的光感受器的基本代谢活动。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测定，我们发现cGMP的慢性积累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。该提议的一个目的是检验谷氨酸耗竭是某些类型的遗传性视网膜变性疾病中光感受器退化的原因的假设。我们将探索营养补充剂可以阻止这些疾病状态的动物模型中的感光细胞变性的可能性。代谢和生存能力也取决于环境。光感受器可以在完整的视网膜中存活数天，但当从视网膜分离时，它们在数小时内退化。该提案的第二个目的是通过表征增强感光细胞存活的小分子的代谢效应来研究解离的感光细胞变性的代谢基础。我们将利用这些信息来帮助确定光感受器的基本代谢要求。

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.