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

• 批准号: 10405079
• 负责人: Alex S Huang
• 金额: $ 41.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405079
• 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 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

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.

项目摘要 青光眼是世界范围内导致永久性视力丧失的主要原因，唯一的治疗方法是降低眼内 压力(眼压)。眼压由房水(眼睛中的液体)离开引流通道的方式决定 从小梁网(TM)开始，然后进入Schlemm管、集电极通道、巩膜内 静脉丛和房水/巩膜上静脉。然而，最近的发现表明，水 幽默流出不是一成不变的，而是比简单的线性描述复杂得多。阿霍 显示动态变量行为(或动态变量流出；DVO)，其中它随分段变化 显示高AHO或低AHO的眼睛区域是动态的，AHO可以自发地增加或 在眼睛的不同位置减少，在药物或手术可以增强的地方是可以改善的。因此， 这项建议旨在通过揭示如何以及为什么可以在某些地区改进AHO来更好地研究DVO 眼睛。这有助于了解疾病中可能丢失了什么，以及降低眼压可能针对哪些目标 治疗。这项提议的中心假设是青光眼疗法对改善DVO有效 通过促进DVO研究并了解这种情况在哪里发生以及如何发生，个性化青光眼 治疗方法可以针对个别患者进行精心设计。为了实现这一点，我们将利用尖端的结构 成像工具，如眼前节光学相干断层扫描(OCT)。我们还将使用一种方法 称为房水血管造影术，这是我们在以前的美国国立卫生研究院和国家眼科研究所上开发的 学院助学金。房水血管造影术使研究人员能够准确地看到房水在 实时的眼睛。利用这些工具，我们将在实验室和供体体内研究体外人眼。 活体眼睛为青光眼和青光眼的治疗带来了最密切的发现。在特定目标(SA1)中， 我们将通过研究节段和节段的结构和分子基础来发现DVO是如何被调控的 在实验室中使用成像和基于屏幕的工具对人供体和离体眼进行动态AHO。在……里面 SA2，我们将使用体外人眼来研究青光眼手术在不同位置对眼睛的影响 降低眼压和近端与远端AHO通路的障碍是手术成功的关键。在SA3中，我们 将调查青光眼药理药物(目前FDA批准的药物配方和交付) 在体外和供体眼睛中改变DVO，特别是观察通过治疗而改善的眼睛部分 理解为什么这些地区有能力这样做。通过这项建议的结果，我们将更好地 了解眼内液体如何离开眼睛的动态过程，以此来增强电流 青光眼治疗，并创造一个跳板，以创新的新方法。