Platform Technologies for Microscopic Retinal Imaging: Development & Translation

 描述(由申请人提供)：治疗退行性视网膜疾病的策略正在快速发展；然而，在实现最终大胆的目标--再生眼睛中的神经元以恢复视力--方面，仍存在重大差距。迫切需要监测活体动物和人类视网膜中单个光感受器和神经节细胞的存在和健康的技术。这些工具将为一些视网膜和神经退行性疾病的发病机制提供关键的洞察力；这种洞察力是为特定患者/疾病开发适当治疗方法的必要第一步。此外，改善了患者细胞结构和功能的可视化 治疗视网膜退行性疾病将使科学家和临床医生能够更准确地瞄准和监测他们的治疗干预措施的结果。我们已经组建了一支多学科的研究团队，他们拥有独特的装备，能够满足这一重大技术需求。凭借我们在开发自适应光学和视网膜成像工具方面的丰富经验，我们建议开发和传播四项互补的平台/使能技术。我们将利用我们在所有五个参与地点之间现有的协作关系、协同专业知识、获得广泛的动物模型以及无与伦比的患者群体来测试这些技术。我们建议开发的具体技术包括：1)实时视网膜运动补偿，即使在极不自主的眼睛运动，如眼球震颤的情况下，也能进行视网膜细胞分辨率成像；2)自适应纵向色差校正，可实现多波长、细胞分辨率的视网膜成像；3)超分辨率行扫描眼底镜，可对以前无法接触到的细胞进行非侵入性成像，并提供自最初的眼科自适应光学演示以来最大的图像分辨率提高(&gt；50%)；以及4)高通量、光生理方法，以细胞分辨率评估光感受器功能，为评估再生/修复细胞的功能提供灵敏的生物标志物。这项应用的一个主要优势是，通过我们的协作网络，我们将在临床前和临床环境中使用再生疗法来验证这些新技术的实用性。这项工作将以前所未有的灵敏度和分辨率诊断视网膜疾病并监测视网膜结构和功能，从而产生重大的积极影响。最后，拟议技术的重点将是光感受器和视网膜神经节细胞成像，以明确地推进这一大胆的目标，但它们将不限于评估任何一种治疗方法或细胞类型。相反，它们将是可推广的，并广泛适用于所有视网膜细胞类型、视网膜疾病和治疗策略。

 DESCRIPTION (provided by applicant): Strategies for treating degenerative retinal diseases are evolving at a rapid pace; however there exist major gaps impeding progress towards the ultimate audacious goal of regenerating neurons in the eye to restore sight. Technologies for monitoring the presence and health of individual photoreceptors and ganglion cells in living animal and human retinae are desperately needed. These tools would provide critical insight into the pathogenesis of a number of retinal and neuro-degenerative diseases; such insight is a requisite first step to developing the appropriate therapeutic approaches for a given patient/disease. Furthermore, improved visualization of cellular structure and function in patients with retinal degenerative diseases will permit scientists and clinicians to more precisely target and monitor the outcome of their therapeutic interventions. We have assembled a multidisciplinary research team uniquely equipped to address this major technological need. Drawing on our extensive experience in developing adaptive optics and retinal imaging tools, we propose to develop and disseminate four complementary platform/enabling technologies. We will leverage our existing collaborative relationships among all five participating sites, synergisic expertise, and access to extensive animal models along with an unrivaled patient population for testing these technologies. The specific technologies we propose to develop are: 1) Real-time retinal motion compensation, allowing retinal cellular-resolution imaging even in cases of extreme involuntary eye motion, like nystagmus; 2) Adaptive longitudinal chromatic aberration correction, allowing multi-wavelength, cellular-resolution retinal imaging; 3) Super- resolution line scanning ophthalmoscopy, to non-invasively image previously inaccessible cells and provide the largest image resolution improvement (> 50%) since the original demonstration of ophthalmic adaptive optics; and 4) High-throughput, opto-physiological method for assessing photoreceptor function with cellular resolution, providing a sensitive biomarker for assessing the function of regenerated/restored cells. A major strength of this application is that through our collaborative network we will validate the utility of these new technologies using regenerative therapies in both pre-clinical and clinical settings. This work will have a significant positive impact by enabling diagnosis of retinal disease and monitoring of retinal structure and function with unprecedented sensitivity and resolution. Finally, the focus of the proposed technologies will be photoreceptor and retinal ganglion cell imaging to explicitly advance the audacious goal, but they will not be limited to assessing any one therapeutic approach or cell type. Rather they will be generalizable and broadly applicable to all retinal cell types, retinal diseases, and therapeutic strategies.