MECHANISMS OF ADAPTATION IN MAMMALIAN CONES

描述（由申请人提供）：锥状光感受器在明亮的光线条件下发挥作用，并且对于具有高时间和空间分辨率的颜色感知和视觉至关重要。值得注意的是，与视杆细胞不同，视锥细胞即使在稳定的明亮光线下也能保持功能，而黑暗则能迅速适应。这两种性质都需要快速回收发色团以再生视锥细胞色素。用于发色团再循环的典型色素上皮途径的生物化学研究和缺点表明可能存在位于视网膜中并且独立于色素上皮的第二种视锥细胞特异性发色团途径。这种途径在生理条件下的功能，其在光感受器生理学中的作用及其调节尚未研究。我们建议使用小鼠光感受器的单细胞和整个视网膜记录来表征这种新的视觉周期的生理功能。具体来说，我们将确定哺乳动物视网膜的能力，以促进色素再生和暗适应锥独立的色素上皮。我们将建立哺乳动物视网膜视觉周期的作用，在背景适应过程中，在扩大动态范围的锥细胞和加速恢复锥细胞的敏感性在暗适应。我们将确定哺乳动物视网膜视觉周期的特异性是否基于视锥细胞而不是视杆细胞将视网膜内循环的11-顺式视黄醇氧化成11-顺式视黄醇并将其用于色素再生的能力。我们将使用现有的转基因小鼠和药理学工具来表征途径中的关键步骤及其通过视网膜中表达的发色团结合蛋白的调节。总的来说，本提案中概述的实验旨在建立使哺乳动物视锥细胞能够在快速变化的光照条件下发挥作用的机制，这是介导白天视觉的光感受器的基本特性。除了推进对视锥细胞生物学的理解，我们对哺乳动物视网膜视觉周期的研究具有潜在的临床意义。本研究中研究的发色团结合蛋白的突变与多种视觉障碍相关，包括Stargardt病、视锥-视杆细胞营养不良和黄斑变性。目前还没有针对这些疾病的治疗方法。我们的实验将为理解视网膜视觉周期中的特定缺陷如何产生视锥相关的视网膜疾病奠定基础，并为开发专门针对视锥功能的新治疗方法奠定基础。

DESCRIPTION (provided by applicant): Cone photoreceptors function under bright light conditions and are essential for color perception and vision with high temporal and spatial resolution. Remarkably, unlike rods, cones remain functional even in steady bright light and dark adapt rapidly. Both of these properties require rapid recycling of chromophore for regeneration of cone visual pigment. Biochemical studies and shortcomings of the canonical pigment epithelium pathway for chromophore recycling indicate the possible existence of a second, cone- specific chromophore pathway located in the retina and independent of the pigment epithelium. The function of such a pathway under physiological conditions, its role in photoreceptor physiology, and its regulation have not been investigated. We propose to use single-cell and whole retina recordings from mouse photoreceptors to characterize the physiological function of this novel visual cycle. Specifically, we will determine the ability of mammalian retina to promote pigment regeneration and dark adaptation in cones independently of the pigment epithelium. We will establish the role of the mammalian retina visual cycle in extending the dynamic range of cones during background adaptation and in accelerating the recovery of cone sensitivity during dark adaptation. We will determine whether the specificity of the mammalian retina visual cycle is based on the ability of cones, and not rods, to oxidize 11-cis retinol, recycled within the retina, into 11-cis retinal and use it for pigment regeneration. We will use available genetically modified mice and pharmacological tools to characterize key steps in the pathway and their modulation by chromophore-binding proteins expressed in the retina. Collectively, the experiments outlined in this proposal seek to establish the mechanisms that enable mammalian cones to function in rapidly varying light conditions, an essential property for the photoreceptors that mediate daytime vision. In addition to advancing the understanding of cone cell biology, our studies of the mammalian retina visual cycle have potential clinical implications. Mutations in the chromophore-binding proteins investigated in this study have been associated with multiple visual disorders including Stargardt disease, cone-rod dystrophy, and macular degeneration. No treatments currently exist for these disorders. Our experiments will lay the foundation for understanding how specific defects in the retina visual cycle produce cone-related retinal disorders, as well as for the development of new treatments targeting specifically the function of cones.