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.

项目摘要 作为视觉的第一步，光感受器具有将光传递到神经信号的关键作用。所以， 通过伤害或疾病，光感受器的任何功能障碍都毁灭了个人的视力。因此， 感光体是许多临床和临床前疗法的靶标，均旨在恢复其功能。 毫不奇怪的是，临床前和临床试验将巨大的价值措施赋予了可以迅速揭示的结果指标 正（或负）功能效应尽快。尽管临床前的爆炸爆炸了 治疗方法，细胞尺度非侵入性，体内功能测定的相对死亡是感光体的 在临床前域中。在这里，我们建议开发非侵入性体内功能工具和技术 从光感受器中获取并验证无对比度的功能信号。 这项研究的目的是：1）使用体内光感受器的基于强度的选择性图表 树sh动物模型，2）量化并增强了重复性，繁殖和吞吐量 在树上的功能成像，3）验证选择性图的“金标准”测量值 使用机械和物理诱导的视网膜的树sh shret shred shred的光感受器功能的功能 退化。我们将通过使用兼容动物的自适应光学扫描激光来解决这些目标 眼镜镜和北方树sh动物模型（Tupaia belangeri）。我们将首先反向翻译 先前从人类到树sh的先前开发的基于强度的选择性图。接下来，我们将建立 可以使用树木中的IORG观察到的最小有意义的变化，评估课程 可重复性，并开发工具以增强小动物模型中的有效成像。最后，我们将利用 树sh动物模型的灵活性研究了我们新生测定敏感测量的能力 药物和机械诱导的残余变性的功能变化。 这项工作的预期结果是建立了一种有价值的功能成像技术 能够评估单个单元格的功能变化并发展的树木 成像工具适用于树sh以外的小动物成像。最终，我们期望这些 促进新型临床前疗法对人类的结果。