Assessing Photoreceptor Structure and Function in Normal and Diseased Retinae

描述(申请人提供)：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，治疗这些毁灭性疾病的前景是一项艰巨的任务。虽然在动物模型中针对这些疾病的治疗策略的开发取得了令人兴奋的进展，但我们目前缺乏直接和 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，迫切需要开发灵敏的、非侵入性的、细胞分辨率技术来评估光感受器的结构和功能。自适应光学成像系统纠正了眼睛的光学像差，允许对活体人类视网膜中的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在细胞尺度上完全非侵入性地探测视网膜功能的可能性。从临床角度来看，这些工具还处于相对婴儿期，我们建议通过以下具体目标帮助加速它们的翻译：1)确定人类色盲患者的治疗潜力，2)确定L和M视蛋白突变如何影响光感受器马赛克的完整性，3)定义视网膜色素变性和Usher综合征患者的视网膜表型，并确定中心凹视锥马赛克的变化如何影响视觉功能和敏感度。之所以选择特定的视网膜变性，是因为它们代表了广泛的视杆和视锥受累，是当前或正在出现的治疗目标，也是我们合作团队的当前优势。这项工作预计将产生重大的积极影响，这里确定的高分辨率基因-表型关系提供了更好地了解遗传性视网膜变性患者的治疗潜力，并产生了通过细胞分辨率评估光感受器结构和功能的有效工具。这项建议解决了NEI出版物《视觉研究：需要、差距和机遇》中确定的三个新兴需求：“表征视网膜黄斑和视网膜中央凹周围区域，以更好地了解黄斑易患疾病的原因”，“将自适应光学等高分辨率视网膜成像技术转化为经济高效且易于使用的临床平台”，以及“开发新的非侵入性成像技术，用于监测体内视网膜神经元的电或代谢活动，理想的是以光感受器的空间分辨率或更高的分辨率来早期检测疾病和监测治疗干预”。

DESCRIPTION (provided by applicant): 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."