OCT Measurement of Trabecular Meshwork Function In Vivo

体内小梁网功能的 OCT 测量

• 批准号: 10480756
• 负责人: C ROSS ETHIER
• 金额: $ 62.14万
• 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/10480756
• 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; hypertensive; 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.

项目摘要/摘要 青光眼是导致失明的主要原因，目前的治疗方法不足。一个严重的，也是唯一可以治疗的 青光眼的危险因素是眼压升高，这通常是由于小梁网(TM)引起的。 功能障碍。值得注意的是，直接评估TM功能的最相关度量，即流出的技术 设施，60多年没有改变，对病人不友好，很少在临床上使用。我们之前的工作是 在人和小鼠的眼睛中建立了TM硬度和流出能力之间的相关性，这强烈地暗示了 TM硬度作为TM函数的替代度量。 在这里，建议开发和验证一种新的基于OCT的方法来测量AS患者的TM硬度 TM功能的间接指标，我们称之为“21世纪色调”。关键的想法是形象地 作为眼压的TM和Schlemm管被操纵。基于这些图像，无偏(自动)OCT图像 分割将被用来量化Schlemm管管腔大小随眼压的变化，然后 工程分析技术(逆有限元建模)将被用来量化 活着的眼睛里的TM。 该提案的初步数据有力地表明，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。第一种使用鼠标模型和 第二种是用人眼。在目标1中，我们将建立我们在对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高眼压模型中使用OCT。这个 由此产生的TM硬度测量将与TM硬度的直接测量进行验证，使用我们的 建立了基于原子力显微镜的方案，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，首先使用灌流的人类前房 组织可以被广泛操纵的节段，然后转移到临床研究中 高眼压/早期青光眼。所有拟议研究的一个重要方面是，临床上- 可用的Rho-Kinase抑制剂(Netarsudil)对TM僵硬、TM功能和眼压进行纵向评估， 加强临床相关性和影响力。正如强劲的初步数据所表明的，预计 提出的基于OCT的TM刚度和TM函数的测量方法将被证明是有效的。 该项目具有很高的创新性，因为它将创造一种新的、非侵入性的工具来询问人类的TM功能 主题，这是自60年前引入色调印刷以来的第一个这样的工具。这样的工具将在以下方面有用 多重背景，包括：(1)TM功能和生理的基础科学研究；(2)纵向 评估新出现的修复TM功能的治疗方法，包括基于小分子的治疗方法、基因 恢复TM功能的治疗方法，以及TM的干细胞疗法。