Transcriptional and Biomechanical Analysis of Segmental Outflow in Glaucoma

青光眼节段流出的转录和生物力学分析

• 批准号: 10327834
• 负责人: C ROSS ETHIER
• 金额: $ 7.87万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327834
• 关键词: Abbreviations; Aftercare; Anatomy; Animals; Anterior; Atomic Force Microscopy; Basic Science; Biomechanics; Blindness; C57BL/6 Mouse; Clinic; Clinical; Clinical Research; Contralateral; Data; Data Set; Dexamethasone; Elements; Engineering; Evaluation; Eye; Functional disorder; Genetic Transcription; 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.

项目摘要/摘要 青光眼是失明的主要原因，目前的治疗不足。主要和唯一的治疗 青光眼的危险因素是眼内压（IOP）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，直接评估最相关测量的技术，即出口流量 设施已有60多年的时间没有变化，不友好，很少在临床上使用。我们先前的工作有 在人和小鼠眼中建立了TM刚度与出口设施之间的相关性，强烈暗示 TM刚度作为TM功能的替代度量。 在这里，建议开发和验证一种基于OCT的新方法，以测量患者的TM刚度 TM函数的间接指标，我们称为“ 21世纪Tonegraphy”的方法。关键的想法是图像 IOP被操纵时TM和Schlemm的运河。基于这些图像，无偏（自动化）OCT图像 分割将用于量化Schlemm的运河腔尺寸的变化，然后 将采用工程分析技术（逆有限元建模）来量化 活着的眼睛中的TM。 该提案的初步数据强烈表明这种方法是可行的。那，总体目标是 验证该方法，这将通过两个特定目标实现。第一个使用鼠标模型和 第二使用人类的眼睛。在AIM 1中，我们将基于我们在成像鼠标出口大道上的丰富经验 在正常动物中具有OCT，并在两种临床上建立的眼高血压模型中。这 最终的TM刚度测量将通过我们的直接测量TM刚度验证 基于原子力显微镜和纵向IOP和出口设施建立的方案 测量。在AIM 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部 可以广泛操纵组织，然后转到患有临床研究的段 眼高血压/早期青光眼。所有提出的研究的一个重要方面是，临床上的影响 在TM刚度，TM功能和IOP上，可用的Rho-激酶抑制剂（NetarSudil）将进行纵向评估， 加强临床相关和影响。正如强大的初步数据所建议的那样，可以预期 提出的基于OCT的测量TM刚度和TM功能的方法将显示为有效。 该项目具有很高的创新性，因为它将创建一种新颖的，无创的工具来询问人类的TM功能 受试者是自六十年前引入Tonegraphy以来的第一个此类工具。这样的工具将在 多种情况，包括：（1）TM功能和生理学的基础科学研究； （2）纵向 评估新的新兴治疗方法以修复TM功能，包括基于小分子的疗法，基因 恢复TM功能的治疗方法和TM基于干细胞的疗法。