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.

项目总结 作为视觉的第一步，光感受器具有将光转化为神经信号的关键作用。因此， 任何因损伤或疾病而导致的光感受器功能障碍都会对个人的视力造成毁灭性的影响。结果, 光感受器是许多临床和临床前治疗的靶点，所有这些都是为了恢复它们的功能。 不足为奇的是，临床前和临床试验将巨大的价值寄托在能够迅速揭示 尽快产生积极的(或消极的)功能影响。尽管真正的临床前疾病爆发 治疗方面，相对缺乏细胞规模的非侵入性体内光感受器功能分析。 在临床前领域。在这里，我们建议开发非侵入性体内功能工具和技术来 获得并验证来自光感受器的无对比度功能信号。 本研究的目的是：1)在活体内利用光感受器来表征基于强度的视网膜图 树鼠动物模型，2)量化和提高重复性、再现性和吞吐量 树鼠的功能成像，以及3)对照“金标准”测量来验证视网膜图 利用机械和药物诱导的视网膜对树鼠视网膜光感受器功能的影响 堕落的人。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 眼底镜和北方树鼠动物模型(Tupaia Belangeri)。我们将首先进行反向翻译 以前开发的基于强度的视网膜图，从人类到树鼠。接下来，我们将建立 使用树精灵中的Iorg可以观察到的最小有意义的变化，评估会话间 重复性，并开发工具，以提高在小动物模型的有效成像。最后，我们将利用 树鼠动物模型的灵活性来研究我们新生的分析方法灵敏地测量 药物和机械诱导的视网膜变性的功能变化。 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 能够在单个细胞水平上评估功能变化并发育的树精 适用于小动物成像的成像工具，超越了树鼠。归根结底，我们期待这些 促进将新的临床前治疗方法转化为人类的结果。