PHOTOTRANSDUCTION IN HEALTH AND DISEASE

摘要 光传导是一种基本的生物过程，涉及一系列的生化反应。 光感受器细胞启动视觉。这项研究计划的长期目标是了解分子 正常和疾病状态下光转导中生化事件的潜在机制。 视紫红质和视锥视蛋白是光感受器细胞中的光感受器，在刺激下启动视觉。 用光。这里主要关注视紫红质的结构、功能和功能障碍。视紫红质起着中枢作用 在光转导中作为信号的发起者发挥作用，在维持健康方面也发挥着重要作用 光感受器细胞。视紫红质基因是导致遗传性视网膜疾病的突变的热点 如视网膜色素变性(RP)和先天性静止性夜盲(CSNB)，目前还没有治愈或 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 提供对这个蛋白质超家族中在结构和结构上具有共性的其他成员的见解 行动机制。尽管视紫红质有丰富的知识可用，但我们的结构和 对受体的分子理解仍然存在，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是不完整的。人们对它的结构、功能和 视锥视蛋白功能障碍，在这里是一个目标的次要焦点。视紫红质结构的三个方面和 在这份提案中将研究其功能。OPSINS必须采用适当的三维结构才能 在光感受器细胞中发挥作用。在目标1中，一组突变体的错误折叠和聚集导致RP和 将对导致蓝色锥体单色性的锥体视蛋白中的突变体进行表征，并由此产生 对小鼠模型视网膜的影响进行了研究。视紫红质在其位置形成超分子结构 在暗视条件下，光感受器细胞的视杆外段的作用。在……里面 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 我们将对这种膜结构进行检查。视紫红质的结构被微调以防止激活 感受器在没有光刺激的情况下。视紫红质的结构性活性可导致多种 引起CSNB或RP的表型。在目标3中，不同表型的分子起源是由 将检查导致视紫红质结构性活性的突变。该提案结合了对 用创新的生物物理和生化方法回答问题的各种转基因小鼠 在每一个目标上都有所提高。我们的研究结果将导致一个更准确的机制框架来理解 系统在正常情况下的功能以及遗传性视网膜疾病中的功能障碍，这将 为科学研究提供新的途径。视紫红质基础研究的长期影响 结构和功能将成为靶向治疗和发现新的药物靶点的可能性。

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.