Non-Invasive Functional Assessments for Translational Retinal Therapeutics

视网膜转化治疗的非侵入性功能评估

• 批准号: 10654125
• 负责人: Robert F Cooper
• 金额: $ 47.91万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654125
• 关键词: Anesthesia procedures; Animal Model; Animals; Appearance; Assessment tool; Biological Assay; Cell Therapy; Cell physiology; Cells; Clinical; Clinical Trials; Cone; Disease; Electroretinography; Etiology; Explosion; Functional Imaging; Functional disorder; Goals; Health; Human; Image; Imaging Device; Imaging Techniques; Individual; Inherited; Injury; Label; Light; Location; Marketing; Measurement; Measures; Mechanics; Modeling; Ophthalmoscopes; Ophthalmoscopy; Optical Coherence Tomography; Optics; Outcome; Outcome Measure; Patients; Photoreceptors; Positioning Attribute; Preclinical Testing; Prognosis; Public Health; Recovery; Reproducibility; Research; Research Personnel; Retina; Retinal Degeneration; Retinal Detachment; Retinal Diseases; Role; Signal Transduction; Software Tools; Structure; Techniques; Technology; Testing; Therapeutic; Time; Translating; Translations; Treatment Efficacy; Tupaia; Tupaiidae; Vision; Visual System; Visualization; Work; adaptive optics; adaptive optics scanning laser ophthalmoscopy; animal imaging; bench to bedside; cost; efficacy evaluation; experience; flexibility; image guided; improved; in vivo; infancy; interest; neurotransmission; non-invasive imaging; novel; pharmacologic; photoreceptor degeneration; postmitotic; pre-clinical; pre-clinical assessment; pre-clinical therapy; preclinical development; preclinical study; preclinical trial; therapy outcome; tool; treatment response

PROJECT SUMMARY As the first step in vision, photoreceptors have the crucial role of transducing light into a neural signal. Therefore, any dysfunction of photoreceptors through injury or disease is devastating to an individual’s vision. As a result, photoreceptors are the target of numerous clinical and preclinical therapies, all aimed at restoring their function. Unsurprisingly, preclinical and clinical trials place enormous value on outcome measures that can quickly reveal positive (or negative) functional effects as quickly as possible. Despite a veritable explosion of preclinical treatments, there is a relative dearth of cellular-scale non-invasive, in vivo functional assays for photoreceptors in the preclinical domain. Here, we propose to develop non-invasive in vivo functional tools and techniques to obtain and validate contrast-free functional signals from photoreceptors. This study aims to: 1) Characterize the intensity-based optoretinogram from photoreceptors in vivo using a tree shrew animal model, 2) Quantify and enhance the repeatability, reproducibility, and throughput of functional imaging in the tree shrew, and 3) Validate the optoretinogram against “gold standard” measurements of photoreceptor function in the tree shrew retina using mechanically and pharmacologically induced retinal degenerations. We will address these goals by use of an animal-compatible adaptive optics scanning laser ophthalmoscope, and the northern tree shrew animal model (Tupaia belangeri). We will first reverse-translate the previously developed intensity-based optoretinogram from humans to the tree shrew. Next, we will establish the minimum meaningful change that can be observed using an iORG in the tree shrew, assess inter-session reproducibility, and develop tools to enhance efficient imaging in small animal models. Finally, we will utilize the flexibility of the tree shrew animal model to investigate the ability of our nascent assays to sensitively measure functional change in pharmacologically and mechanically induced retinal degenerations. The expected outcomes of this work are to have established a valuable functional imaging technique in the tree shrew that is capable of assessing functional change at the level of an individual cell, and to develop imaging tools that are applicable to small animal imaging beyond the tree shrew. Ultimately, we expect these outcomes to facilitate the translation of novel preclinical therapies to humans.

项目概要 作为视觉的第一步，光感受器在将光转换为神经信号方面发挥着至关重要的作用。 由于受伤或疾病而导致的任何感光器功能障碍都会对个人的视力造成破坏。 光感受器是许多临床和临床前治疗的目标，所有这些治疗的目的都是恢复其功能。 毫不奇怪，临床前和临床试验对能够快速揭示结果的指标具有巨大的价值 尽管临床前确实出现了爆炸式的增长，但仍尽快产生积极（或消极）的功能影响。 治疗中，细胞尺度的非侵入性体内光感受器功能测定是一个亲密的亲戚 在临床前领域，我们建议开发非侵入性体内功能工具和技术。 获取并验证来自光感受器的无对比功能信号。 本研究的目的是： 1) 使用体内光感受器来表征基于强度的视视网膜图 树鼩动物模型，2) 量化并提高重复性、再现性和通量 树鼩的功能成像，以及 3) 根据“金标准”测量验证验光视网膜图 使用机械和药理学诱导的视网膜来研究树鼩视网膜中的光感受器功能 我们将通过使用动物兼容的自适应光学扫描激光器来实现这些目标。 检眼镜和北方树鼩动物模型（Tupaia belangeri）我们将首先进行反向翻译。 接下来，我们将建立先前开发的从人类到树鼩的基于强度的视视网膜图。 使用 iORG 在树鼩中观察到的最小有意义的变化，评估会话间 再现性，并开发工具来增强小动物模型的有效成像。 树鼩动物模型的灵活性，以研究我们的新生检测方法灵敏测量的能力 药理和机械引起的视网膜变性的功能变化。 这项工作的预期成果是建立一种有价值的功能成像技术 树鼩能够评估单个细胞水平的功能变化，并开发 最终，我们期望有适用于树鼩之外的小动物成像的成像工具。 促进将新型临床前疗法转化为人类的成果。