Assessing Photoreceptor Structure and Function in Normal and Diseased Retinae

描述（由申请人提供）：在美国，遗传性视网膜变性影响大约1/1500的个体，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病症的治疗策略的开发方面已经取得了令人兴奋的进展，但我们目前缺乏直接和有效的工具。 立即评估各种干预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且宏观。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感光细胞的结构和功能。自适应光学成像系统校正眼睛的光学像差，允许对活体人类视网膜中的个体视杆和视锥感光细胞进行成像。此外，同样的自适应光学工具，用于图像的感光马赛克提供了潜在的探测视网膜功能的细胞规模，完全非侵入性。从临床的角度来看，这些工具还处于相对的婴儿期，我们建议通过以下具体目标来帮助加速它们的转化：1）确定在患有色盲的人类患者中的治疗潜力，2）确定L和M视蛋白突变如何影响光感受器镶嵌的完整性，以及3）确定患有视网膜色素变性和Usher综合征的患者中的视网膜表型，并确定中央凹锥镶嵌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细胞和视锥细胞受累，是治疗工作的当前或新兴目标，也是我们合作团队的当前优势。这项工作预计将产生显着的积极影响，这里确定的高分辨率基因型-表型关系提供了对遗传性视网膜变性患者治疗潜力的更好理解，并产生了经验证的工具，用于评估感光体结构和功能与细胞分辨率。该提案解决了NEI出版物“视觉研究：需求，差距和机会”中确定的3个新兴需求：“表征视网膜的黄斑和中央凹周围区域，以更好地了解黄斑对疾病的偏好”，“将高分辨率视网膜成像技术（如自适应光学）转化为用于常规临床使用的具有成本效益且易于使用的平台”，以及“开发新颖的，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，理想地以光感受器的空间分辨率或更好地用于疾病的早期检测和治疗干预的监测。"

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."