Understanding Mustard Vesicants Distribution and Toxicity in the Eye Using In Vivo and In Silico Models

使用体内和计算机模型了解芥末糜烂剂在眼中的分布和毒性

• 批准号: 10709188
• 负责人: Carrie German
• 金额: $ 46.7万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709188
• 关键词: Acute; Address; Affect; Animal Testing; Animals; Aqueous Humor; Biochemical; Bioinformatics; Biological; Biological Markers; Blindness; Bulla; Clinical; Computer Models; Cornea; Corneal Injury; DNA; Data; Development; Dose; Evaluation; Eye; Eye Injuries; Future; Grant; Inflammation; Injury; Keratopathy; Knowledge; Laboratories; Liquid substance; Mass Spectrum Analysis; Mechlorethamine; Minor; Modeling; Molecular; Mustard; Mustard Gas; Ocular Pathology; Organ; Oryctolagus cuniculus; Pathologic; Pathology; Pathway interactions; Penetration; Phase; Process; Publishing; Recording of previous events; Reporting; Research; Retina; Severities; Study models; Symptoms; Syria; Terrorism; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicokinetics; Translating; Translations; Validation; Vesicants; Visual impairment; Vitreous humor; adduct; analog; biomarker evaluation; chemical threat; conjunctiva; corneal repair; cost; design; effective therapy; experimental study; improved; in silico; in vivo; injured; injury and repair; nerve agent; novel; novel strategies; repaired; response; response biomarker; retinal toxicity; therapeutic evaluation; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; treatment strategy; wound healing

Project Summary Mustard vesicating agent sulfur mustard (SM) is the most extensively used warfare agent in history and remains a potential agent of warfare and terrorism. Eye is the most sensitive organ to SM and its analog nitrogen mustard (NM) exposure, resulting in devastating biphasic injury called Mustard Gas Keratopathy. The dose- and time- related severity of symptoms and the mechanism of this biphasic injury involving damage to the most affected cornea and possibly to other ocular tissues is not well understood. In addition, the extent to which mustard vesicants distribute, transport, and persist in various tissues of the eye is largely unknown, which could further identify tissue specific toxicity effects, injury progression and repair process. Such studies could aid in the identification of effective treatment strategies to counter tissue specific acute and long-term ocular complications from mustard vesicants’ exposure, which are elusive. To address this knowledge gap, we will use a synergistic in vivo-in silico approach to determine mustard vesicant ocular distribution and the ensuing corneal injury and repair mechanisms. We will leverage CFD Research’s existing in silico rabbit ocular model that is currently being used to characterize the distribution related toxicity of various chemical threat agents. Using the published data, preliminary in silico modeling studies show that NM penetrates well beyond the cornea. We hypothesize that a synergistic novel in vivo-in silico approach will assist in understanding how mustard vesicants distribute in healthy eyes and the mechanism by which the ocular injury develops, persists, and recovers or reappears as long-term complications. To support this hypothesis, the proposed specific aims will first computationally model NM (SM surrogate used in laboratory settings) related ocular injury and then translate this to simulate SM exposure. Aim 1: Determine Ocular Distribution of Nitrogen Mustard for Various Exposure Scenarios. The computational model will be validated on NM toxicokinetic (TK) profiles from in vivo rabbit studies and then extrapolated within the experimentally tested range to obtain TK profiles for non-tested NM exposure scenarios. Aim 2: Identify Relevant Biomarkers, Mechanisms and Pathways of NM-Induced Corneal Injury Progression and Repair. The combination of time- and dose-dependent transcriptomics and biomarker evaluation, as well as the NM TK analysis proposed under Aim 1, may contribute to determine the pathological mechanisms underlying early and late corneal injury development, progression, and repair related to vesicant bi-phasic keratopathy. Aim 3: Translation of the In Silico NM Rabbit Ocular Model to Simulate SM Exposure. The preliminary evaluations could assess comparisons of in Silico SM corneal injury model with NM, and serve as a vital step for minor alterations or in designing animal studies for additional validation under future studies. A combination of in silico and in vivo studies could serve as a more efficient and potentially more insightful novel approach to evaluate tissue-specific toxicity mechanisms underlying the mustard vesicants’ ocular pathology, and to identify therapeutic strategies that can improve the clinical mustard keratopathy symptoms and enhance wound healing.

项目摘要 芥末发泡剂硫磺芥末(SM)是历史上使用最广泛的战剂，至今仍在使用 战争和恐怖主义的潜在代理人。眼睛是对SM及其类似物氮芥酸最敏感的器官 (NM)暴露，导致破坏性的双相损伤，称为芥子气角膜病。剂量和时间- 相关症状的严重程度和这种双相损伤的机制，包括对受影响最严重的人的损害 对角膜和可能对其他眼组织的影响还不是很清楚。此外，芥末的程度 发泡剂在眼睛的各种组织中的分布、运输和持续存在在很大程度上是未知的，这可能会进一步 确定特定的组织毒性效应、损伤进展和修复过程。这样的研究可能有助于 确定有效的治疗策略以对抗特定组织的急性和长期眼部并发症 由于芥末发泡剂的暴露，这是难以捉摸的。为了解决这一知识鸿沟，我们将使用协同 体内硅胶方法确定芥子气发泡剂的眼部分布和随之而来的角膜损伤 修复机制。我们将利用CFD Research现有的硅胶兔眼模型，目前正在 用于表征各种化学威胁剂的分布相关毒性。使用发布的数据， 电子计算机模型的初步研究表明，NM的穿透性远远超出了角膜。我们假设一个 协同作用新的体内-体内硅胶方法将有助于了解芥末发泡剂如何在健康人体内分布 眼睛和眼睛损伤发展、持续和恢复或再现的机制是长期的 并发症。为了支持这一假设，提出的具体目标将首先对NM(SM)进行计算建模 实验室环境中使用的替代物)与眼部损伤相关，然后将其转换为模拟SM暴露。目标 1：确定不同暴露情景下氮芥的眼睛分布。计算性的 模型将根据活体兔研究中的NM毒代动力学(TK)曲线进行验证，然后在 实验测试的范围，以获得未测试的NM暴露场景的TK配置文件。目标2：确定 NM诱导的角膜损伤进展和修复的相关生物标志物、机制和途径。 时间和剂量依赖的转录组学和生物标志物评估的组合，以及NM TK 在目标1下提出的分析可能有助于确定早期和 与发泡性双相角膜病变相关的晚期角膜损伤的发生、发展和修复。目标3： 翻译In Silico NM兔眼模型以模拟SM暴露。初步评估 可以评估In Silico SM角膜损伤模型与NM模型的比较，并作为Minor的关键步骤 改变或设计动物研究，以便在未来的研究中进行额外的验证。In Silico的组合 体内研究可以作为一种更有效、可能更有洞察力的新方法来评估 芥末发泡剂眼部病理的组织特异性毒性机制，并鉴定 可改善临床芥子气角膜病变症状，促进伤口愈合的治疗策略。