Assessing Photoreceptor Structure and Function in Normal and Diseased Retinae

遗传性视网膜变性在美国大约每1500人中就有1人受到影响，而且 治疗这些毁灭性的疾病是一项艰巨的任务。虽然在这方面取得了令人振奋的进展 在动物模型中开发针对这些疾病的治疗策略，目前我们缺乏敏感的工具来 直接和立即评估各种干预措施可能如何影响人类患者的视网膜健康- 用于评估视网膜结构和功能的临床工具相对不敏感和宏观。因此， 迫切需要开发敏感的、非侵入性的、细胞分辨率的技术来评估 光感受器的结构和功能。自适应光学成像系统对眼睛的光学校正 像差，允许对活体人类视网膜中单个视杆细胞和视锥感光细胞进行成像。 此外，用于成像光感受器马赛克的自适应光学工具提供了探测的可能性 视网膜在细胞尺度上的功能，完全非侵入性。从临床的角度来看，这些工具正在 相对处于起步阶段，我们建议通过以下具体目标帮助加速翻译：1) 确定人类色盲患者的治疗潜力，2)确定L和M视如何 突变影响光感受器马赛克的完整性，以及3)确定患者的视网膜表型 视网膜色素变性和Usher综合征，并确定中心凹视锥马赛克的变化如何影响视力 功能和灵敏度。之所以选择特定的视网膜退行性变是因为它们代表了广泛的范围 视杆和视锥的参与，是当前或正在出现的治疗努力的目标，是目前的优势 我们的协作团队。这项工作预计将产生重大的积极影响，具有高分辨率 这里确定的基因型-表型关系提供了对治疗潜力的更好的理解 在遗传性视网膜变性患者中，以及生产有效的工具来评估光感受器 具有细胞分辨率的结构和功能。该提案解决了以下3个新需求 NEI的出版物《视觉研究：需要、差距和机遇》： 为了更好地了解黄斑的发病倾向，视网膜中央凹周围区域 分辨率视网膜成像技术，如自适应光学，转化为经济高效且易于使用的平台 常规临床使用“和”开发新的，非侵入性的成像技术，以监测电或代谢 活体视网膜神经元的活动，理想的是以光感受器的空间分辨率或更好的早期检测 疾病监测和治疗干预监测。

Inherited retinal degenerations affect approximately 1 in 1,500 individuals in the US, and the prospect of treating these devastating diseases is a daunting task. While exciting progress has been made in the development of therapeutic strategies for these conditions in animal models, we currently lack sensitive tools to directly and immediately assess how various interventions might affect retinal health in human patients - clinical tools for assessing retinal structure and function are relatively insensitive and macroscopic. As such, there is a critical need to develop sensitive, noninvasive, cellular-resolution techniques for assessing photoreceptor structure and function. Adaptive optics imaging systems correct for the eye's optical aberrations, allowing imaging of individual rod and cone photoreceptor cells in the living human retina. Moreover, the same adaptive optics tools used to image the photoreceptor mosaic offer the potential to probe retinal function on a cellular scale, completely noninvasively. From a clinical perspective, these tools are in relative infancy, and we propose to help accelerate their translation through the following specific aims: 1) Define the therapeutic potential in human patients with achromatopsia, 2) Determine how L and M opsin mutations affect the integrity of the photoreceptor mosaic, and 3) Define the retinal phenotype in patients with retinitis pigmentosa and Usher syndrome, and determine how changes in the foveal cone mosaic affect visual function and sensitivity. The specific retinal degenerations were chosen because they represent a wide range of rod and cone involvement, are current or emerging targets for treatment efforts, and are a current strength of our collaborative team. This work is expected to have a significant positive impact, with the high-resolution genotype-phenotype relationships identified here providing a better understanding of the therapeutic potential in patients with inherited retinal degenerations as well as producing validated tools for assessing photoreceptor structure and function with cellular resolution. This proposal addresses 3 emerging needs identified in the NEI's Publication, "Vision Research: Needs, Gaps, and Opportunities": "Characterize the macula and perifoveal regions of the retina to better understand the predilection of the macula for disease," "Translate high- resolution retinal imaging technologies, like adaptive optics, into cost-effective and easy-to-use platforms for routine clinical use," and "Develop novel, noninvasive imaging techniques for monitoring electrical or metabolic activity of retinal neurons in vivo, ideally at the spatial resolution of photoreceptors or better for early detection of disease and monitoring of therapeutic intervention."