Dynamic Variable Aqueous Humor Outflow and Glaucoma Therapies in the Human Eye

人眼的动态可变房水流出和青光眼治疗

基本信息

批准号：
10155489
负责人：
Alex S Huang
金额：
$ 14.81万
依托单位：
DOHENY EYE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155489
关键词：
Acetylcholine Affect Angiography Anterior Aqueous Humor Area Behavior Biology Blindness Brain Death Bypass Carbachol Cell Death Characteristics Ciliary Muscle Complex Coupled Disease Distal Drainage procedure Drug Delivery Systems Drug Formulations Drug Targeting Endothelin-1 Engineering Excision Eye FDA approved Future Genomics Glaucoma Goals Grant Histologic Human Image Imaging Device Individual Institutional Review Boards Laboratories Liquid substance Location Measures Methods Molecular Movement Muscarinics National Eye Institute Nitric Oxide Operating Rooms Operative Surgical Procedures Optical Coherence Tomography Optics Organ Donor Pathway interactions Patient Care Patients Pattern Perfusion Pharmaceutical Preparations Pharmacological Treatment Pharmacology Physiologic Intraocular Pressure Physiological Pilocarpine Process Proteomics Protocols documentation Regulation Research Research Personnel Resources Retinal Ganglion Cells Rho-associated kinase Risk Factors Route Science Structure Structure of sinus venosus of sclera Study models System Time Trabecular meshwork structure Tracer Translating United States United States National Institutes of Health Veins Venous Vision Work aqueous base cholinergic clinical care drug development experimental study glaucoma surgery human model human tissue improved in vivo individual patient innovation kinase inhibitor novel novel therapeutics personalized medicine real-time images response success tool

项目摘要

Project Summary Glaucoma is a leading cause of permanent vision loss worldwide, and the only treatment is to lower intraocular pressure (IOP). IOP is governed by how aqueous humor (the fluid in the eye) exits the drainage pathways that start at the trabecular meshwork (TM) before moving into Schlemm’s canal, collector channels, an intrascleral venous plexus, and aqueous/episcleral veins. However, recent discoveries have demonstrated that aqueous humor outflow (AHO) is not static and unchanging but is more complex than a simple linear depiction. AHO shows dynamic variable behavior (or dynamic variable outflow; DVO) where it is variable with segmental regions of the eye displaying high- or low-AHO, is dynamic where AHO can spontaneously increase or decrease in different locations of the eye, and is improvable where drugs or surgeries can enhance it. Thus, this proposal aims to better study DVO by uncovering how and why AHO can be improved in certain regions of the eye. This helps understand what may have been lost in disease and what may be targeted in IOP-lowering treatments. The central hypothesis in this proposal is that glaucoma therapies work at improvable DVO regions and that by facilitating DVO research and knowing where and how this occurs, personalized glaucoma treatments can be crafted for individual patients. To accomplish this, we will utilize cutting edge structural imaging tools such as anterior segment optical coherence tomography (OCT). We will also use a method called aqueous angiography that we developed on a previous National Institutes of Health and National Eye Institute grant. Aqueous angiography allows researchers to see exactly where aqueous humor is flowing in the eye in a real-time fashion. With these tools, we will study ex vivo human eyes in the laboratory and in donor in vivo eyes to yield the most germane discoveries for glaucoma and glaucoma treatment. In Specific Aim (SA1), we will discover how DVO is regulated by studying the structural and molecular basis of segmental and dynamic AHO using imaging and screen-based tools on human donor and ex vivo eyes in the laboratory. In SA2, we will use ex vivo human eyes to study how glaucoma surgeries in different locations in the eye impact IOP lowering and what hurdles the proximal vs. distal AHO pathways present to surgical success. In SA3, we will investigate how glaucoma pharmacological drugs (currently FDA-approved drug formulations and delivery) alter DVO in ex vivo and donor eyes, specifically looking at the parts of the eye that are improved by treatment to understand why these areas had the capacity to do so. Through the results of this proposal, we will better understand the dynamic processes of how intraocular fluid leaves the eye as a way to enhance current glaucoma treatments and to create a springboard to innovate new ones.

项目概要青光眼是全世界永久性视力丧失的主要原因，唯一的治疗方法是降低眼压眼压 (IOP) 取决于房水（眼睛中的液体）如何排出引流通道。从小梁网 (TM) 开始，然后进入施累姆氏管、收集通道、巩膜内然而，最近的发现表明房水/巩膜外静脉。幽默流出（AHO）不是静态和不变的，而是比简单的线性描述更复杂。显示动态变量行为（或动态变量流出；DVO），其中它是分段变量显示高或低 AHO 的眼睛区域是动态的，其中 AHO 可以自发增加或减少眼睛不同部位的情况会有所减少，并且可以通过药物或手术来改善，因此，该提案旨在通过揭示如何以及为何在某些地区改进 AHO 来更好地研究 DVO 这有助于了解疾病中可能损失的部分以及降低眼压的目标。该提案的中心假设是青光眼疗法可改善 DVO。通过促进 DVO 研究并了解这种情况发生的地点和方式，个性化青光眼为了实现这一目标，我们将利用尖端的结构。我们还将使用一种方法，例如眼前段光学相干断层扫描（OCT）。称为水性血管造影，是我们在以前的美国国立卫生研究院和国家眼科研究所的基础上开发的研究所资助。房水血管造影使研究人员能够准确地看到房水在哪里流动。借助这些工具，我们将在实验室和供体中研究离体人眼。体内眼睛在青光眼和青光眼治疗方面取得了最密切的发现（SA1），我们将通过研究片段和分子的结构和分子基础来发现 DVO 是如何被调节的。在实验室中使用基于成像和屏幕的工具对人类供体和离体眼睛进行动态 AHO。 SA2，我们将使用离体人眼来研究青光眼手术对眼睛不同位置的影响在 SA3 中，IOP 降低以及近端 AHO 通路与远端 AHO 通路对手术成功的阻碍因素。将研究青光眼药理药物如何（目前FDA批准的药物配方和递送）改变离体和供体眼睛的 DVO，特别是观察通过治疗得到改善的眼睛部分了解为什么这些领域有能力这样做，通过这个建议的结果，我们会更好。了解眼内液如何离开眼睛的动态过程，以此增强电流青光眼治疗并创建创新新疗法的跳板。