Modulation of cone photoreceptor function by autophagy

自噬调节视锥光感受器功能

• 批准号: 10681018
• 负责人: Thomas Almon Ferguson
• 金额: $ 41.29万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681018
• 关键词: Ablation; Acceleration; Acute; Affect; Autophagocytosis; Blindness; Bypass; Cells; Cellular Stress; Cone; Dark Adaptation; Darkness; Data; Degradation Pathway; Disease; Electrophysiology (science); Electroretinography; Eukaryotic Cell; Exercise; Exposure to; Fasting; Future; Genetic; Health; Homeostasis; Human; Intermittent fasting; Kinetics; Light; Link; Measures; Mediating; Metabolic; Metabolism; Muller' s cell; Mus; Natural regeneration; Pathway interactions; Photoreceptors; Physical Exercise; Physiological; Play; Predisposition; Process; Recovery; Recycling; Reporter; Retinal Cone; Retinal Degeneration; Retinal Pigments; Rod; Role; Signal Transduction; Starvation; Stress; Structure of retinal pigment epithelium; Synaptic Transmission; Testing; Up-Regulation; Vertebrate Photoreceptors; Vision; Visual; Work; chromophore; experimental study; in vivo; light effects; novel; prevent; response; translational study; visual cycle

ABSTRACT Autophagy is a lysosomal degradation pathway that maintains cellular homeostasis under basal and stress conditions by catabolizing cellular constituents to produce energy and building blocks. Although autophagy is common to all eukaryotic cells, highly specialized cells exploit this pathway to support their unique physiological functions. One such example is cone photoreceptors, where autophagy promotes survival during periods of metabolic or light-induced stress. The function of cones as our daytime photoreceptors depends critically on the rapid recovery of their sensitivity after exposure to bright light, a process known as dark adaptation. This metabolically-demanding process is driven by the turnover of chromophore for the regeneration of cone visual pigment and by the resetting of the efficiency of synaptic transmission between cones and cone bipolar cells. As autophagy is intimately involved in cellular metabolism, we will test the novel hypothesis that autophagy modulates the cone-driven photopic dark adaptation. We will perform experiments to determine the physiological conditions that activate autophagy in cones, focusing on bright light exposure, fasting, and physical exercise. We will also determine the subcellular compartments in cones where autophagy is upregulated in response to a range of stress conditions. To investigate the role of autophagy in cone-driven photopic dark adaptation, we will perform electrophysiological experiments to determine how fasting, exercise, or genetic block of autophagy affect the recovery of photopic function following exposure to bright light. Finally, we will evaluate two alternative mechanisms by which autophagy could be modulating photopic dark adaptation, either by accelerating the turnover of visual chromophore or by enhancing synaptic transmission. These experiments will establish autophagy as a novel mechanism for regulating the function of mammalian cone photoreceptors and photopic vision. They will also pave the way for future translational studies with humans seeking to prevent vision loss and enhance photopic vision by intermittent fasting or exercise.

摘要 自噬是一种溶酶体降解途径，其在基础和基础水平下维持细胞内稳态。 通过分解细胞成分来产生能量和构建块来胁迫条件。虽然 自噬是所有真核细胞所共有的，高度特化的细胞利用这一途径来支持它们的自噬。 独特的生理功能。一个这样的例子是锥状光感受器，自噬促进 在代谢或光诱导应激期间的存活。视锥细胞的功能就像我们的白天 光感受器主要依赖于在暴露于强光后其灵敏度的快速恢复， 这就是所谓的暗适应。这一代谢要求很高的过程是由 视锥细胞视色素再生和突触效率的重新设置， 视锥细胞和视锥双极细胞之间的传递。由于自噬与细胞内的 代谢，我们将测试新的假设，自噬调节锥驱动的明视暗 适应我们将进行实验来确定激活自噬的生理条件 在锥体中，专注于强光照射，禁食和体育锻炼。我们还将确定 视锥细胞中的亚细胞区室，其中自噬响应于一系列应激而上调 条件为了研究自噬在视锥细胞驱动的明视暗适应中的作用，我们将进行 电生理学实验，以确定禁食，运动或自噬的遗传阻断如何影响 暴露在强光下后明视功能的恢复。最后，我们将评估两个备选方案， 自噬可以调节明视暗适应的机制， 视觉发色团的周转或通过增强突触传递。这些实验将 建立自噬作为调节哺乳动物视锥细胞光感受器功能的新机制 和明视觉它们还将为未来的人类翻译研究铺平道路， 通过间歇性禁食或锻炼来预防视力下降和增强明视视力。