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.

眼睛比其他器官容易暴露于囊泡剂的10倍。这些后果暴露及其对人类视力的影响很容易低估，因为许多眼症状可能暴露后很长时间表现出来。这就是有记录在伊拉克 - 伊朗战争不仅在袭击发生后的最初30小时内遭受了角膜损害 40年后，Scotopic和Photopic ElectorEtinogran图响应减少。此外，症状延迟这些人还包括中央视网膜静脉阻塞和泪流下固体VEGF-A的增加。当前，没有有效的解毒剂来打击囊泡引起的眼部损害和人类视力丧失。因此，我们的长期目标是产生有效的医疗对策，以减轻这样的暴露。除非我们提高分子理解对导致眼部损害和渐进性眼损伤的基本机制由囊泡造成接触。因此，在此提案中，我们分析了直接的眼暴露（DOE），以识别vesicant 分子信号传导驱动角膜，血管和视网膜病理生物学的急性和慢性阶段。专注关于展开的蛋白质反应（UPR）-TRIB3下游信号传导，我们假设在DOE上，不仅角膜组织，以及其他眼组织，例如血管和残留组织，被损坏，并且根据严重程度，囊泡暴露激活角膜中的UPR-TRIB3信号，进一步传播VEGF信号，引起血管功能障碍和视网膜损伤。剖析机械链接在直接眼暴露和病理生理学之间，我们提出了分散策略的不同范围以及广泛的工具。这些工具包括不同的动物模型（小鼠和树sh），角膜和视网膜外组织，角膜和视网膜培养细胞，两种不同的毒物（刘易斯石和氮芥末），和角膜，血管和残留组织中Trib3的遗传消融，以阻止Trib3-VEGF信号和延迟眼部损伤的发作。后者将在囊泡暴露动物的实验中得到确认用小分子抑制剂VEGF-TRAP-EYE处理。因此，在AIM＃1中，我们建议调查是否 DOE到Vesicant的动物激活UPR-Trib3-VEGF轴，充当角膜组织损伤的分子驱动器。我们将证明角膜原始的Trib3-VEGF轴激活的分子后果。在AIM＃2中，我们打算确定分泌的角膜部落3介导的VEGF信号是否通过评估角膜新血管形成（NV）和视网膜血管破坏。在AIM＃3中，我们计划调查分泌的角膜和血管介导的VEGF是否通过视网膜损伤的病理生理 UPR-TRIB3的激活。这些研究将通过激活的UPR-TRIB3-VEGF轴是眼组织病理学的分子驱动器为暴露人群中的眼毒性提供基础，以实现未来的机械研究。