Molecular Mechanisms of Photoreceptor Adaptation

光感受器适应的分子机制

基本信息

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
项目类别：
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&apos 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

项目摘要

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”.

项目摘要当单杆和锥形光感受器吸收光并产生一个时，我们的视力开始电信号，较高的大脑中心，然后分析以改变我们的行为。我们甚至学到棒的孩子是我们用来看到昏暗的光线和圆锥体的光感受器，以看到明亮的光线和颜色。这视图受到行为测量和电气记录的支持，这似乎都表明杆是首先用于检测昏暗的光，并随着环境照明的增加而实质上是非功能的在白天。然而，最近的实验挑战了这一观念，并证明了杆可以即使在如此强烈的光线下继续做出响应，以至于将大部分的杆显影作物漂白。这些观察挑战了我们在明亮的光线下对杆功能的理解。这项研究的目的是彻底重新检查杆电流和对持续的明亮照明的电压响应时间的持续时间。我们的初步证据表明，杆的响应能力可以恢复在持续的明亮照明期间的时间里。在这里，我们试图调查该杆恢复的分子和机械基础及其对小鼠的时间和光强度的依赖。特别是，我们将利用具有针对性突变成分的几行转基因小鼠光转导级联。我们也对如何在杆上进行光电恢复感兴趣如在锥体中所观察到的，更快，更健壮。我们将通过基因探索这些现象通过利用与小鼠的相关小鼠，将锥形光转导的某些分子特征转移到棒中靶向突变，以降低杆的灵敏度并提高光响应速率和照相的速率衰变。我们希望表明哪些因素是两者的差异反应的原因光感受器在明亮的光线下。这些现象不仅对我们对光感受器的生理学，它们对于光感受器存活也是必不可少的，因为杆在外部时死亡细分频道的关闭时间过长。此外，了解如何制作杆由于锥体视觉的缺陷可能会减轻，因此更像锥体的感光器可能具有治疗价值通过将杆的响应能力转移到更明亮的背景光强度上。由于重要性这些现象与光感受器在健康和疾病中的功能，NEI的视网膜疾病计划它是其计划目标之一，用于“分析光适应和恢复的机制遵循光转移”。