PHOTOTRANSDUCTION IN HEALTH AND DISEASE

健康和疾病中的光传导

• 批准号: 10374486
• 负责人: Paul S Park
• 金额: $ 42.12万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374486
• 关键词: Adopted; Atomic Force Microscopy; Biochemical; Biochemical Reaction; Biological Assay; Biological Process; Biophysics; Cell physiology; Cells; Cellular biology; Chemicals; Classification; Clinical; Cone; Defect; Disease; Equilibrium; Event; Fluorescence Resonance Energy Transfer; Functional disorder; G-Protein-Coupled Receptors; Genes; Genetic; Goals; Health; Hot Spot; In Vitro; Inherited; Knock-in Mouse; Knowledge; Lead; Light; Link; Membrane; Membrane Proteins; Methods; Molecular; Molecular Chaperones; Mus; Mutation; Nature; Night Blindness; Opsin; Pathogenesis; Phenotype; Photoreceptors; Phototransduction; Physiological; Physiology; Play; Point Mutation; Process; Property; Proteins; Receptor Activation; Research; Retina; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Retinoids; Rhodopsin; Rod; Rod Outer Segments; Role; Scheme; Scientific Inquiry; Severities; Signal Transduction; Site; Structure; System; Testing; Vision; Vision Disorders; Visual system structure; base; blue cone monochromacy; combat; effective therapy; in vivo; innovation; insight; member; mouse model; mutant; nanoscale; new technology; new therapeutic target; novel; novel strategies; photoreceptor cell outer segment; prevent; programs; protein structure function; receptor; response; retinal rods; rod outer segment disc; success; targeted treatment; three dimensional structure; tool

Abstract Phototransduction is a fundamental biological process involving a set of biochemical reactions in photoreceptor cells initiating vision. The long-term goal of this research program is to understand the molecular mechanisms underlying the biochemical events in phototransduction under normal and diseased states. Rhodopsin and cone opsins are the light receptors in photoreceptors cells that initiate vision upon stimulation by light. The primary focus here is on rhodopsin structure, function and dysfunction. Rhodopsin plays a central role in phototransduction as the initiator of signaling and also plays an important role in maintaining the health of photoreceptor cells. The rhodopsin gene is a hot spot for mutations causing inherited retinal diseases such as retinitis pigmentosa (RP) and congenital stationary night blindness (CSNB), which currently have no cure or effective treatment. Rhodopsin is a prototypical G protein-coupled receptor and therefore findings here can provide insights on other members of this superfamily of proteins that share commonalities in structure and mechanisms of action. Despite the wealth of knowledge available for rhodopsin, gaps in our structural and molecular understanding of the receptor still exist and a mechanistic description on the effect of mutations in the light receptor causing vision disorders is incomplete. Less is known about the structure, function, and dysfunction of cone opsins, a secondary focus here in one aim. Three aspects of rhodopsin structure and function will be examined in this proposal. Opsins must adopt a proper three-dimensional structure for proper function in photoreceptor cells. In aim 1, the misfolding and aggregation of a set of mutants that cause RP and a mutant in a cone opsin causing blue cone monochromacy will be characterized, and the resulting consequences in the retina of mouse models examined. Rhodopsin forms a supramolecular structure at its site of action in the rod outer segment of photoreceptor cells to carry out its function under scotopic conditions. In aim 2, the dynamics of this supramolecular structure will be visualized and the impact of diseased states on this membrane organization will be examined. The structure of rhodopsin is finely tuned to prevent activation of the receptor in the absence of light stimulation. Constitutive activity of rhodopsin can lead to a variety of phenotypes causing CSNB or RP. In aim 3, the molecular origin of the different phenotypes caused by mutations causing constitutive activity in rhodopsin will be examined. The proposal combines the study of a variety of genetically modified mice with innovative biophysical and biochemical methods to answer questions raised in each aim. Results from our studies will lead to a more accurate mechanistic framework to understand the function of the system under normal conditions and dysfunctions in inherited retinal diseases, which will provide new avenues for scientific inquiry. The long-term impact in studying fundamental aspects of rhodopsin structure and function will be the potential for targeted therapeutics and discovery of novel drug targets.

抽象的 光转导是一个基本的生物过程，涉及一系列生化反应 感光细胞启动视觉。该研究计划的长期目标是了解分子 正常和患病状态下光转导生化事件的机制。 视紫红质和视锥细胞视蛋白是感光细胞中的光受体，在受到刺激时启动视觉 通过光。这里的主要焦点是视紫红质的结构、功能和功能障碍。视紫红质发挥着中枢作用 作为信号传导的引发剂在光转导中发挥作用，并且在维持健康方面也发挥着重要作用 感光细胞。视紫红质基因是导致遗传性视网膜疾病（例如 例如视网膜色素变性（RP）和先天性静止性夜盲症（CSNB），目前尚无治愈方法或 有效的治疗。视紫红质是一种典型的 G 蛋白偶联受体，因此这里的发现可以 提供有关该蛋白质超家族其他成员的见解，这些成员在结构和 行动机制。尽管我们对视紫红质有丰富的知识，但我们在结构和 对受体的分子理解仍然存在，并且对突变影响的机制描述仍然存在 导致视力障碍的光感受器不完整。人们对它的结构、功能和作用知之甚少。 视锥细胞视蛋白功能障碍，这是这里的一个目标的第二个焦点。视紫红质结构的三个方面 本提案将审查功能。视蛋白必须采用适当的三维结构才能发挥适当的作用 在感光细胞中发挥作用。在目标 1 中，一组突变体的错误折叠和聚集导致 RP 和 造成蓝色视锥细胞单色性的视锥细胞视蛋白突变体将被表征，并且由此产生的 对所检查的小鼠模型的视网膜产生的影响。视紫红质在其位点形成超分子结构 感光细胞视杆外段的作用，以在暗视条件下发挥其功能。在 目标 2，这种超分子结构的动力学将被可视化，以及疾病状态对 将检查该膜组织。视紫红质的结构经过精细调整，可防止激活 受体在没有光刺激的情况下。视紫红质的组成活性可导致多种 导致 CSNB 或 RP 的表型。在目标 3 中，由以下因素引起的不同表型的分子起源： 将检查引起视紫红质组成型活性的突变。该提案结合了一项研究 多种转基因小鼠用创新的生物物理和生化方法回答问题 在每个目标中提出。我们的研究结果将带来更准确的机制框架来理解 正常情况下系统的功能和遗传性视网膜疾病的功能障碍，这将 为科学探究提供新的途径。研究视紫红质基本方面的长期影响 结构和功能将成为靶向治疗和发现新药物靶点的潜力。