Optoretinography: All-optical measures of functional activity in the human retina

视网膜检光术：人类视网膜功能活动的全光学测量

• 批准号: 10295296
• 负责人: DANIEL V PALANKER
• 金额: $ 103.79万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295296
• 关键词: Action Potentials; Affect; Age; Animals; Automobile Driving; Basic Science; Biological Assay; Biological Markers; Biomedical Engineering; Biophysical Process; Cell Culture Techniques; Cell model; Cells; Cellular Structures; Clinic; Clinical; Collection; Computer Models; Cone; Data; Data Analyses; Detection; Diagnosis; Disease; Electrophysiology (science); Electroretinography; Elements; Event; Evolution; Eye; Eye diseases; Foundations; Functional disorder; Generations; Goals; Gold; Grant; Human; Human Volunteers; Image; Individual; Interferometry; Ions; Lateral; Light; Location; Machine Learning; Measurement; Measures; Membrane; Methods; Monitor; Motion; Natural regeneration; Neurons; Noise; Optics; Patients; Pharmacology; Phase; Photic Stimulation; Photoreceptors; Phototransduction; Physiological; Physiology; Plant Roots; Positioning Attribute; Property; Research; Resolution; Retina; Retinal Cone; Retinal Degeneration; Retinal Diseases; Rodent; Rodent Model; Scanning; Signal Transduction; Site; Solid; Speed; Stimulus; System; Techniques; Technology; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Transgenic Model; Translations; Treatment Efficacy; Universities; Vision; Visual system structure; Washington; adaptive optics; adaptive optics scanning laser ophthalmoscopy; analog; base; cell type; cellular imaging; clinical application; computerized data processing; data acquisition; design; efficacy evaluation; ganglion cell; imaging approach; in vivo; inherited retinal degeneration; millisecond; multi-electrode arrays; mutant; nanometer; non-invasive imaging; patch clamp; relating to nervous system; repaired; response; retinal neuron; spatiotemporal; temporal measurement; tool; visual dysfunction; visual processing; visual tracking

Project Summary/Abstract The last few decades have seen major inroads into detailing the physiological mechanisms supporting vision as well as therapies aimed at rescue and repair of neurons affected by retinal diseases. For the continued evolution of treatments and their rapid translation to the clinic, it is essential to find a non-invasive, all-optical biomarker to monitor the efficacy of disease and potential therapeutic agents. To this end, we propose to develop the optoretinogram, or ORG, the optical analog to the electroretinogram (ERG) which is the current gold standard for retinal function assessment in humans. The ORG is rooted in classical interferometry and enables a highly sensitive assay of how neurons interact with light. Using this technique, our group has demonstrated the ability to visualize light-driven neural activity across a range of spatiotemporal resolution – from single cells to a collection of neurons, and from µsecs to ms timescales. Here, we aim to expand the capabilities of the ORG and demonstrate its efficacy for basic science and clinical applications. The proposed technology is built upon a solid foundation of established approaches, and combines them in new and complementary ways to achieve an optimal combination of speed, resolution and sensitivity geared towards overcoming the key challenges faced with imaging cellular structure-function in humans. The core technologies are phase-resolved OCT, an eye-safe, interferometric method to measure nm-scale changes at ms time scales in vivo, adaptive optics (AO) to overcome ocular aberrations, increase the signal-to-noise and allow resolution down to single cells and real-time eye tracking to overcome eye motion and allow targeting, recording and averaging of responses from single and a collection of retinal neurons. These are implemented across three ORG platforms. At the University of Washington, we will refine the line-scan phase-resolved OCT with improvements in optical design and eye-tracking and use it to characterize the basic properties of phototransduction and inner retinal function in healthy human volunteers and patients with retinal degenerations. At Stanford University, we will develop a similar line-scan system for rodents, and together with transgenic models and pharmacology, determine the biophysical mechanisms that underlie the ORG and develop templates for human recordings. At UC Berkeley, we will push the envelope of speed and sensitivity by incorporating a real-time eye-tracking system to drive an AO-OCT interferometric probe, with the aim to measure the tiniest and briefest neuronal changes in the human retina. This bioengineering research partnership will benefit from complementary expertise, research direction and ORG implementation across the three sites, and the use of common approaches for image/data analysis, eye tracking and visual stimulation. Ultimately, the aggregate technology will facilitate a deeper mechanistic understanding of early visual processing and eye disease, and provide entirely new avenues for accelerating therapeutic interventions.

项目总结/摘要 在过去的几十年里，人们对支持视觉的生理机制进行了深入研究 以及旨在挽救和修复受视网膜疾病影响的神经元的疗法。为继续 随着治疗方法的发展及其在临床上的快速应用，必须找到一种非侵入性的、全光学的 生物标志物来监测疾病和潜在治疗剂的功效。为此，我们建议 开发视光视网膜图，或ORG，与视网膜电图（ERG）的光学模拟， 人类视网膜功能评估的金标准。ORG植根于经典的干涉测量法， 能够高度灵敏地分析神经元如何与光相互作用。利用这项技术，我们的团队 展示了在一系列时空分辨率上可视化光驱动神经活动的能力- 从单个细胞到神经元的集合，从微秒到毫秒的时间尺度。在这里，我们的目标是扩大 ORG的能力，并证明其在基础科学和临床应用中的功效。拟议 技术是建立在一个坚实的基础上的既定方法，并结合他们在新的， 以互补的方式实现速度、分辨率和灵敏度的最佳组合， 克服了人类细胞结构-功能成像所面临的关键挑战。核心技术 是相位分辨OCT，一种人眼安全的干涉测量方法，可以在ms时间测量nm尺度的变化 自适应光学（AO）克服了眼像差，增加了信噪比， 分辨率下降到单个细胞和实时眼动跟踪，以克服眼睛运动，并允许瞄准， 记录和平均来自单个和一组视网膜神经元的反应。加以实施 三个ORG平台。在华盛顿大学，我们将改进行扫描相位分辨OCT 在光学设计和眼动跟踪方面有所改进，并利用它来表征 健康志愿者和视网膜病变患者的光传导和视网膜内功能 退化在斯坦福大学，我们将为啮齿动物开发一个类似的线扫描系统，并与 转基因模型和药理学，确定ORG的生物物理机制， 为人类录音制作模板。在加州大学伯克利分校，我们将推动速度和灵敏度的信封 通过结合实时眼睛跟踪系统来驱动AO-OCT干涉仪探头，目的是 测量人类视网膜中最微小的神经元变化。这项生物工程研究 合作伙伴关系将受益于互补的专业知识，研究方向和ORG的实施， 三个网站，并使用常见的方法进行图像/数据分析，眼睛跟踪和视觉刺激。 最终，聚合技术将促进对早期视觉的更深层次的机械理解。 这一新的技术将为加速治疗干预提供全新的途径。