Molecular Mechanisms of Photoreceptor Adaptation

光感受器适应的分子机制

• 批准号: 10337225
• 负责人: Alapakkam P Sampath
• 金额: $ 40.49万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337225
• 关键词: Behavior; Bradyopsia; Brain; Calmodulin; Child; Color; Cone; Cone dystrophy; Dependence; Disease; Electrodes; Evaluation; Exposure to; Eye; GRK1 gene; Genetic Engineering; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Hour; Inherited; Investigation; Learning; Leber' s amaurosis; Light; Light Adaptations; Lighting; Macular degeneration; Mammals; Measurement; Mediating; Microspectrophotometry; Molecular; Mus; Mutation; National Eye Institute; Natural regeneration; Night Blindness; Phosphorylation; Photons; Photoreceptors; Phototransduction; Physiological; Physiology; Pigments; Process; Proteins; Psychophysics; Recovery; Reporting; Retina; Retinal Cone; Retinal Diseases; Retinal Pigments; Retinoids; Rhodopsin; Rod; Role; Signal Transduction; Suction; Therapeutic; Time; Transducin; Transgenic Mice; United States National Institutes of Health; Vertebrate Photoreceptors; Vision; Work; absorption; base; behavior measurement; experimental study; interest; light intensity; partial recovery; patch clamp; photoreceptor degeneration; prevent; programs; recoverin protein; response; retinal rods; voltage

Project Summary Our sense of vision begins when single rod and cone photoreceptors absorb light and produce an electrical signal, which higher centers in the brain then analyze to alter our behavior. We learn even as children that rods are the photoreceptors we use to see dim light and cones to see bright light and color. This view is supported by behavioral measurements and electrical recording, which all seem to show that rods are primarily used to detect dim light and become essentially non-functional as the ambient illumination increases during daylight. Recent experiments have however challenged this notion and demonstrated that rods can continue to respond even in light so strong that a large fraction of the rod photopigment is bleached. These observations challenge our understanding of rod function in bright light. The purpose of this study is to thoroughly reexamine rod current and voltage responses to persistent bright illumination over extended durations of time. Our preliminary evidence shows surprisingly that the responsiveness of rods can recover over the course of hours during persistent bright illumination. Here we are seeking to investigate the molecular and mechanistic basis of this rod recovery and its dependence on time and light intensity in mice. In particular, we will leverage several lines of transgenic mice having targeted mutations in components of the phototransduction cascade. We also are interested in how photoresponse recovery in rods can be made faster and more robust, as observed in cones. We we will explore these phenomena by genetically transferring certain molecular features of cone phototransduction into the rods by leveraging mice with targeted mutations to reduce the sensitivity of rods and increase the rate of photoresponse and photopigment decay. We hope to show which factors are responsible for the differential responsiveness of the two photoreceptors in bright light. These phenomena are not only important to our understanding of the physiology of photoreceptors, they are also essential for photoreceptor survival because rods die when outer- segment channels remain closed for too long a time. In addition, understanding how to make rod photoreceptors more like cones may have therapeutic value, as deficiencies in cone vision may be mitigated by shifting the responsiveness of rods to brighter background light intensities. Because of the importance of these phenomena to photoreceptor function in health and disease, the Retinal Disease Program of the NEI has as one of its program objectives to “analyze the mechanisms underlying light adaptation and recovery following phototransduction”.

项目摘要 当单个杆状和锥状感光器吸收光线并产生 电信号，它是大脑的高级中枢，然后进行分析以改变我们的行为。我们甚至在学习的时候 孩子们认为，视杆是我们用来看到暗淡光线的感光器，视锥是用来看到明亮光线和颜色的。这 这一观点得到了行为测量和电记录的支持，所有这些似乎都表明，杆子 主要用于检测暗淡的光线，并随着环境照明的增加而变得基本不起作用 在白天。然而，最近的实验挑战了这一概念，并证明了棒子可以 即使在如此强烈的光线下也会继续做出反应，以至于杆状光致色素的很大一部分被漂白。这些 观测结果挑战了我们对强光下杆状函数的理解。这项研究的目的是 彻底重新检查棒电流和电压对过长持续明亮照明的响应 持续时间。我们的初步证据令人惊讶地显示，杆状细胞的反应性可以恢复。 在持续明亮的照明期间的几个小时内。在这里，我们试图调查 在小鼠中，这种杆状恢复的分子和机制基础以及它对时间和光照强度的依赖。 特别是，我们将利用几个转基因小鼠品系，这些转基因小鼠的部分成分具有靶向突变 光传导级联。我们还对如何在棒中进行光响应恢复感兴趣。 更快、更结实，如在圆锥体中观察到的。我们我们将从遗传学的角度来探索这些现象 将锥体光传导的某些分子特征通过利用小鼠的 靶向突变降低视杆的敏感度，提高光反应和光变色的速度 腐烂。我们希望说明是哪些因素导致了两者的不同反应。 在强光下的光感受器。这些现象不仅对我们理解 光感受器的生理学，它们对光感受器的生存也是必不可少的，因为杆状细胞在外部- 段通道保持关闭的时间太长。此外，了解如何制作棒材 更像视锥细胞的光感受器可能具有治疗价值，因为视锥细胞视力的缺陷可能会得到缓解。 通过将棒的响应性转换为更亮的背景光强度。因为……的重要性 这些现象对光感受器在健康和疾病中的作用，NEI的视网膜疾病计划 将分析光适应和恢复的潜在机制作为其计划目标之一 在光转导之后“。