Molecular Mechanisms of Photoreceptor Adaptation

光感受器适应的分子机制

• 批准号: 10558643
• 负责人: Alapakkam P Sampath
• 金额: $ 41.74万
• 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/10558643
• 关键词: Acceleration; Behavior; Bradyopsia; Brain; Breeding; Calmodulin; Cells; Child; Color; Cone; Cone dystrophy; Darkness; Dependence; Disease; Electrodes; Evaluation; Exposure to; Eye; GRK1 gene; Genetic Engineering; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Hour; Inherited; Investigation; Isomerism; 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; behavior measurement; experimental study; interest; light intensity; overexpression; 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 我们的视觉开始于单个视杆和视锥光感受器吸收光并产生一个光信号。 电子信号，大脑中的高级中心然后分析以改变我们的行为。我们学习，即使 儿童视杆细胞是我们用来看到暗淡光线的光感受器，而视锥细胞是用来看到明亮光线和颜色的光感受器。这 这种观点得到了行为测量和电记录的支持，它们似乎都表明， 主要用于检测昏暗的光线，并且随着环境照明的增加而变得基本上不起作用 在白天。然而，最近的实验挑战了这一概念，并证明杆可以 即使在如此强烈的光线下也能继续反应，以至于大部分杆细胞色素被漂白。这些 观测挑战了我们对强光下视杆功能的理解。本研究的目的是 彻底重新检查棒电流和电压对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表明，反应杆可以恢复 在持续明亮的照明下持续数小时。在这里，我们试图调查 这种杆恢复的分子和机制基础及其对小鼠中的时间和光强度的依赖性。 特别是，我们将利用几种转基因小鼠的品系，这些小鼠的基因组成分中具有靶向突变。 光转导级联我们也对如何恢复视杆细胞的光反应感兴趣 更快，更强大，正如在锥体中观察到的那样。我们将通过遗传学的方法来探索这些现象 将视锥细胞光转导的某些分子特征转移到视杆细胞中， 靶向突变，以降低视杆细胞的敏感性，增加光反应和色素沉积的速率 腐烂我们希望能说明是哪些因素导致了两者的反应性差异 光感受器在强光下这些现象不仅对我们理解 光感受器的生理学，它们也是光感受器生存所必需的，因为当外部光感受器的时候， 分段通道保持关闭的时间过长。此外，了解如何使杆 更像视锥细胞的光感受器可能具有治疗价值，因为可以减轻视锥细胞视觉的缺陷。 通过改变视杆细胞对更亮的背景光强度的反应。由于重要性， 这些现象对健康和疾病中的感光体功能的影响，NEI的视网膜疾病项目 作为其计划目标之一，“分析光适应和恢复的机制 光传导后”。