OCT Measurement of Trabecular Meshwork Function In Vivo

体内小梁网功能的 OCT 测量

• 批准号: 10222709
• 负责人: C ROSS ETHIER
• 金额: $ 59.8万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222709
• 关键词: Abbreviations; Aftercare; Anatomy; Animals; Anterior; Atomic Force Microscopy; Basic Science; Blindness; C57BL/6 Mouse; Clinic; Clinical; Clinical Research; Contralateral; Data; Data Set; Dexamethasone; Elements; Engineering; Evaluation; Eye; Functional disorder; Glaucoma; Glossary; Goals; Health; Human; Hypertension; Image; Location; Measurement; Measures; Mediating; Methods; Modeling; Mus; Newly Diagnosed; Ocular Hypertension; Organ Culture Techniques; Outcome; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Pharmacology; Physiologic Intraocular Pressure; Physiological; Physiology; Pliability; Primary Open Angle Glaucoma; Protocols documentation; Resistance; Rho-associated kinase; Risk; Risk Factors; Structure of sinus venosus of sclera; Techniques; Testing; Time; Tissues; Trabecular meshwork structure; Tracer; Transforming Growth Factor Beta 2; Treatment Efficacy; Validation; Virus; Work; aqueous; base; clinically relevant; cohort; drinking water; experience; experimental study; fluid flow; gene therapy; human subject; imaging Segmentation; improved; in vivo; innovation; kinase inhibitor; mouse model; non-invasive imaging; normotensive; novel; novel strategies; overexpression; pressure; repaired; response; small molecule; stem cell therapy; tonometry; tool

Project Summary/Abstract Glaucoma is a major cause of blindness and current treatments are insufficient. A major and the only treatable risk factor for glaucoma is elevated intraocular pressure (IOP), which is usually due to trabecular meshwork (TM) dysfunction. Remarkably, techniques for directly assessing the most relevant measure of TM function, i.e. outflow facility, have not changed for 60+ years, are patient-unfriendly, and are rarely used clinically. Our prior work has established a correlation between TM stiffness and outflow facility in human and mouse eyes, strongly implicating TM stiffness as a surrogate measure of TM function. Here it is proposed to develop and validate a novel OCT-based method to measure TM stiffness in patients as an indirect indicator of TM function, an approach we term “21st century tonography”. The key idea is to image the TM and Schlemm’s canal as IOP is manipulated. Based on these images, unbiased (automated) OCT image segmentation will be used to quantify the change of Schlemm’s canal luminal size as a function of IOP, and then engineering analysis techniques (inverse finite element modeling) will be employed to quantify the stiffness of the TM in the living eye. The proposal’s preliminary data strongly suggest that this approach is feasible. Thus, the overall objective is to validate the approach, which will be achieved through two specific aims. The first uses mouse models and the second uses human eyes. In Aim 1, we will build on our extensive experience in imaging the mouse outflow tract with OCT in normotensive animals and in two clinically-relevant established models of ocular hypertension. The resulting TM stiffness measurements will be validated against direct measurements of TM stiffness using our established protocol based on atomic force microscopy, and against longitudinal IOP and outflow facility measurements. In Aim 2, we will carry out analogous studies in human eyes, first using perfused human anterior segments where the tissue can be extensively manipulated, and then moving to clinical studies in patients with ocular hypertension/early glaucoma. An important aspect of all proposed studies is that the effects of a clinically- available rho-kinase inhibitor (netarsudil) on TM stiffness, TM function, and IOP will be longitudinally assessed, strengthening clinical relevant and impact. It is expected, as suggested by the strong preliminary data, that the proposed OCT-based approach to measuring TM stiffness and TM function will be shown to be valid. This project is highly innovative, since it will create a novel, non-invasive tool to interrogate TM function in human subjects, the first such tool since the introduction of tonography six decades ago. Such a tool will be useful in multiple contexts, including: (1) basic science studies of TM function and physiology; and (2) longitudinal evaluation of novel emerging treatments to repair TM function, including small molecule-based therapies, gene therapy approaches for restoring TM function, and stem cell-based therapies for the TM.

项目概要/摘要 青光眼是导致失明的主要原因，目前的治疗方法还不够。一个主要且唯一可治疗的 青光眼的危险因素是眼压 (IOP) 升高，这通常是由小梁网 (TM) 引起的 功能障碍。值得注意的是，直接评估 TM 功能最相关测量值（即流出）的技术 设施60多年来没有改变，对患者不友好，临床上很少使用。我们之前的工作有 建立了人类和小鼠眼睛的 TM 硬度和流出设施之间的相关性，强烈暗示 TM 刚度作为 TM 函数的替代度量。 这里建议开发并验证一种基于 OCT 的新方法来测量患者的 TM 硬度： TM 功能的间接指标，我们将这种方法称为“21 世纪断层扫描”。关键思想是图像 当 IOP 被操纵时，TM 和 Schlemm 管。基于这些图像，无偏（自动）OCT 图像 分割将用于量化施累姆氏管管腔尺寸随 IOP 的变化，然后 将采用工程分析技术（逆有限元建模）来量化 活人眼睛里的TM。 该提案的初步数据强烈表明这种方法是可行的。因此，总体目标是 验证该方法，这将通过两个具体目标来实现。第一个使用鼠标模型， 第二个使用人眼。在目标 1 中，我们将利用我们在小鼠流出道成像方面的丰富经验 在血压正常的动物和两个临床相关的已建立的高眼压模型中使用 OCT 进行研究。这 由此产生的 TM 刚度测量结果将使用我们的 TM 刚度直接测量结果进行验证 建立了基于原子力显微镜的协议，并针对纵向眼压和流出设施 测量。在目标 2 中，我们将在人眼中进行类似的研究，首先使用灌注的人前眼 可以对组织进行广泛操作的部分，然后转向患者的临床研究 高眼压/早期青光眼。所有拟议研究的一个重要方面是临床效果 将纵向评估可用的 rho 激酶抑制剂（netarsudil）对 TM 硬度、TM 功能和 IOP 的影响， 加强临床相关性和影响力。正如强劲的初步数据所示，预计 所提出的基于 OCT 的测量 TM 刚度和 TM 函数的方法将被证明是有效的。 该项目具有高度创新性，因为它将创建一种新颖的非侵入性工具来探究人类 TM 功能 这是自六年前推出断层扫描以来第一个此类工具。这样的工具将很有用 多种背景，包括：（1）TM功能和生理学的基础科学研究； (2)纵向 评估修复 TM 功能的新兴疗法，包括基于小分子的疗法、基因疗法 恢复 TM 功能的治疗方法，以及基于干细胞的 TM 疗法。