The mechanism of vesicant-induced ocular injury

起泡剂引起的眼损伤的机制

基本信息

批准号：
10687105
负责人：
Marina Gorbatyuk
金额：
$ 44.55万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10687105
关键词：
Ablation Acute Affect Agreement Animal Model Animals Antidotes Apoptotic Automobile Driving Blindness Blood Vessels Bulla Cell Death Cessation of life Chemical Warfare Agents Chronic Cornea Corneal Injury Corneal Neovascularization Corneal Opacity Cultured Cells Data Development Dose Electroretinography Endothelial Cells Epithelial Cells Exposure to Extravasation Eye Eye Injuries Functional disorder Future Genetic Goals Harvest Homologous Gene Human Individual Inflammation Injury Iran Iraq Link Mechlorethamine Mediating Mediator Molecular Mus Mustard Gas Organ Oxides Pathogenesis Penetration Photophobia Photoreceptors Population Predisposition Proteins Publishing Reporting Respiratory System Retina Retrospective Studies Severities Signal Transduction Skin Survivors Symptoms Time Tissues Tupaiidae Up-Regulation VEGF Trap VEGFA gene Vascular Endothelial Growth Factors Vascularization Vegf Inhibitor Vesicants Vision War central retinal vein occlusion combat corneal epithelium experience experimental study healing lewisite medical countermeasure neovascularization novel overexpression prevent response retina blood vessel structure retinal toxicity small molecule inhibitor tissue injury tool toxicant transmission process vascular injury

项目摘要

The eye is 10 times more susceptible to exposure to vesicants than other organs. The aftermath of these exposures and their impacts on human vision are easy to underestimate since many ocular symptoms may manifest long after exposure. Thus, it has been documented that the survivors of a vesicant attack during the Iraq–Iran War not only experienced corneal damage in the first 30 h after the attack but also manifested diminished scotopic and photopic electroretinogram responses 40 years later. In addition, delayed symptoms in these individuals also included central retinal vein occlusion and an increase of soluble VEGF-A in their tears. Currently, there is no effective antidote to combat vesicant-induced ocular damage and vision loss in humans. Therefore, our long-term goal is to generate effective medical countermeasures to mitigate the consequences of such exposures. This goal will not be achievable unless we increase our molecular understanding of the underlying mechanism responsible for the ocular damage and progressive ocular injuries caused by vesicant exposure. Therefore, in this proposal, we analyze direct ocular exposure (DOE) to vesicants to identify the molecular signaling driving the acute and chronic stages of corneal, vascular, and retinal pathobiology. Focusing on the unfolded protein response (UPR)-TRIB3 downstream signaling, we hypothesize that, upon DOE, not only the corneal tissue but also other ocular tissues, such as vascular and retinal tissues, are damaged, and depending on the severity, vesicant exposure activates UPR-TRIB3 signaling in the cornea, which further propagates the VEGF signal, causing blood vessel dysfunction and retinal injury. To dissect the mechanistic link between direct ocular exposure and pathophysiology, we propose a diverse spectrum of step-by-step strategies and a broad arsenal of tools. These tools include different animal models (mice and tree shrews), corneal and retinal ex vivo tissue, corneal and retinal cultured cells, two different toxicants (lewisite and nitrogen mustard), and genetic ablation of TRIB3 in the corneal, vascular, and retinal tissue to block the TRIB3-VEGF signal and delay the onset of ocular injuries. The latter will be confirmed in experiments with vesicant-exposed animals treated with a small-molecule inhibitor VEGF-Trap-Eye. Therefore, in Aim #1, we propose to investigate whether DOE to vesicants activates the UPR-TRIB3-VEGF axis, acting as a molecular driver of corneal tissue injury. We will demonstrate the molecular consequences of corneal-originated TRIB3-VEGF axis activation. In Aim #2, we intend to determine whether secreted corneal TRIB3-mediated VEGF signal drives vascular pathogenesis by assessing corneal neovascularization (NV) and retinal blood vessel disruption. In Aim #3, we plan to investigate whether secreted cornea- and vascular-mediated VEGF drives the pathophysiology of retinal injury through the activation of UPR-TRIB3. These studies will identify a novel and highly interesting molecular mechanism by which the activated UPR-TRIB3-VEGF axis acts as a molecular driver of ocular tissue pathobiology and will establish a groundwork for future mechanistic studies of ocular toxicity in exposed populations.

眼睛接触出疱剂的可能性比其他器官高出 10 倍。暴露及其对人类视力的影响很容易被低估，因为许多眼部症状可能会因此，有记录显示，在暴露后很长一段时间里，有出疱疹发作的幸存者。两伊战争不仅在袭击发生后的前30小时内出现了角膜损伤，而且还表现出 40 年后，暗视和明视视网膜电图反应减弱。这些人还存在视网膜中央静脉阻塞以及泪液中可溶性 VEGF-A 的增加。目前，尚无有效的解毒剂来对抗起泡剂引起的人类眼部损伤和视力丧失。因此，我们的长期目标是制定有效的医疗对策以减轻后果除非我们增加对分子的了解，否则这个目标将无法实现。起泡剂引起的眼损伤和进行性眼损伤的潜在机制因此，在本提案中，我们分析了对出疱剂的直接眼部暴露 (DOE)，以确定出疱剂的暴露程度。驱动角膜、血管和视网膜病理学急性和慢性阶段的分子信号传导。关于未折叠蛋白反应 (UPR)-TRIB3 下游信号传导，我们发现，根据 DOE，不仅角膜组织以及其他眼组织，例如血管和视网膜组织都受到损害，并且根据严重程度，接触出泡剂会激活角膜中的 UPR-TRIB3 信号传导，从而进一步传播 VEGF 信号，导致血管功能障碍和视网膜损伤。剖析其中的机制联系。在直接眼部暴露和病理生理学之间，我们提出了多种分步策略以及广泛的工具库，这些工具包括不同的动物模型（小鼠和树鼩）、角膜和视网膜离体组织、角膜和视网膜培养细胞、两种不同的毒物（路易斯和氮芥）、以及角膜、血管和视网膜组织中 TRIB3 的基因消融，以阻断 TRIB3-VEGF 信号和延迟眼部损伤的发生将在接触起泡剂的动物的实验中得到证实。因此，在目标#1 中，我们建议研究是否可以使用小分子抑制剂 VEGF-Trap-Eye。 DOE 对出疱剂激活 UPR-TRIB3-VEGF 轴，充当角膜组织损伤的分子驱动因素。将展示角膜起源的 TRIB3-VEGF 轴激活的分子后果在目标#2 中，我们。旨在确定分泌的角膜 TRIB3 介导的 VEGF 信号是否通过以下方式驱动血管发病机制评估角膜新生血管 (NV) 和视网膜血管破坏在目标 3 中，我们计划进行调查。分泌的角膜和血管介导的 VEGF 是否通过以下途径驱动视网膜损伤的病理生理学：这些研究将通过以下方式确定一种新颖且非常有趣的分子机制。激活的 UPR-TRIB3-VEGF 轴充当眼组织病理学的分子驱动因素，并将为未来暴露人群眼毒性的机制研究奠定基础。