Toxic Mechanisms of Vesicating Chemicals in the Eye

眼内起泡化学物质的毒性机制

• 批准号: 10676306
• 负责人: Patrick Michael McNutt
• 金额: $ 46.28万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10676306
• 关键词: Accidents; Acute; Autopsy; Biological; Biological Assay; Biological Markers; Bulla; Cadaver; Cataract; Cell Death; Cessation of life; Chemical Injury; Chemicals; Clinical; Cornea; Corneal Injury; DNA; Development; Dose; Exposure to; Eye; Eye Injuries; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Histologic; Human; India; Industrialization; Inflammatory; Injury; Laboratories; Lesion; Liquid substance; Long-Term Effects; Longitudinal Studies; Measures; Methods; Modeling; Molecular; Molecular Target; Monitor; Mustard Gas; Optical Coherence Tomography; Organ Culture Techniques; Oryctolagus cuniculus; Outcome; Pathology; Pathway interactions; Penetration; Physiological; Poison; Population; Predisposition; Productivity; Prognosis; Property; Proteins; Proteome; Public Health; RNA; Recovery; Research Personnel; Risk; Risk Assessment; Route; Structure; Survivors; System; Therapeutic; Thick; Tissue-Specific Gene Expression; Tissues; Toxic effect; Toxicology; Translating; Vesicants; Vision; Visual impairment; Volatilization; absorption; adduct; chemical threat; chemokine; clinical examination; corneal epithelial wound healing; corneal epithelium; corneal regeneration; corneal scar; covalent bond; cytokine; cytotoxic; cytotoxicity; epithelium regeneration; experience; healing; in vivo; innovation; mass casualty; methyl isocyanate; neovascularization; programs; response; response to injury; small molecule; therapeutic target; transcriptome; transcriptomics; vapor; wound healing

PROJECT SUMMARY/ABSTRACT The cornea is highly susceptible to injury from chemotoxic vapors. Long-term prognosis after severe corneal injury is poor, involving impaired vision, progressive corneal decompensation and neovascularization. In particular, ocular injuries caused by the formation of chemical adducts between biological molecules and highly reactive organic toxic industrial materials (TIMs) remain poorly characterized. The ocular threat caused by organic TIMs was illustrated in Bhopal, India in 1984, when the accidental release of methyl isocyanate resulted in over 3,700 deaths and 500,000 casualties, with 4,000 survivors suffering permanently disabling ocular pathophysiologies such as corneal scars, opacities and cataracts. In this proposal we will characterize the dose- dependent, acute and long-term effects of diverse, highly reactive organic TIMs on corneal injury and recovery. The approach integrates in vivo methods developed to study corneal toxicities elicited by the archetypal vesicant sulfur mustard with ex vivo approaches pioneered to study the corneal effects of exposure to diverse chemotoxic agents. We will focus on TIMs that are widely availability in large quantities and thus pose a large-scale chemotoxic threat following accidental or purposeful release. In the first aim, we will integrate the ex vivo depth- of-injury exposure model with our well-described vapor cap exposure system to determine TIM vapor doses that produce mild and severe corneal lesions in isolated rabbit eyes. In the second aim, we will translate dose estimates to in vivo eyes in rabbits and study molecular, clinical and pathophysiological mechanisms of corneal injury over 8 weeks. In the final aim, we will compare and contrast (a) acute changes in gene expression in human and rabbit eyes exposed to superficial and penetrating doses of three TIMs and (b) study longitudinal changes in gene expression in vivo following exposure to penetrating doses of 3 TIMs. By studying the toxic effects of diverse reactive TIMs, we will develop a threat profile based on dose, tissue-specific cytotoxicities, pathophysiological progression and efficacy of available therapeutics. In addition to identifying toxicological mechanisms and expanding our understanding of chemotoxic injury in the cornea, these studies will inform risk assessments and exposure management plans for these highly toxic organic TIMs and related chemicals.

项目摘要/摘要 角膜非常容易受到趋化毒性造成的损伤。严重角膜后的长期预后 损伤很差，涉及视力受损，进行性角膜代偿作用和新血管形成。在 特别是，由生物分子之间的化学加合物形成和高度 反应性有机有毒工业材料（TIM）的特征仍然很差。由 1984年在印度博帕尔（Bhopal）说明了有机蒂姆斯（Tims 在3,700多人的死亡和500,000人伤亡中，有4,000名幸存者永久性破坏眼 病理生理，例如角膜疤痕，不透明和白内障。在此提案中，我们将表征剂量 - 多样化，高反应性有机TIM对角膜损伤和恢复的依赖性，急性和长期影响。 该方法整合了用于研究原型囊泡的角膜毒性开发的体内方法 硫芥末酱采用体内方法率先研究，以研究暴露于趋化性毒性的角膜作用 代理商。我们将重点关注大量可用性的TIM，从而构成大规模 意外或有目的释放后的介绍性威胁。在第一个目标中，我们将整合离体深度 - 与我们描述良好的蒸气帽曝光系统的受伤暴露模型，以确定蒂姆蒸气剂​​量 在孤立的兔眼中产生轻度和严重的角膜病变。在第二个目标中，我们将翻译剂量 兔子体内眼睛的估计和研究角膜的分子，临床和病理生理机制 在8周内受伤。在最终目标中，我们将比较和对比（a）基因表达的急性变化 人类和兔子的眼睛暴露于三个TIM的表面和穿透剂量，（b）研究纵向 暴露于3个TIM的渗透剂量后，体内基因表达的变化。通过研究有毒 不同反应性蒂姆斯的影响，我们将根据剂量，组织特异性细胞毒性发展威胁特征， 可用治疗剂的病理生理进展和功效。除了识别毒理学 机制并扩展了我们对角膜中介质毒性损伤的理解，这些研究将为风险提供信息 评估和暴露管理计划针对这些剧烈的有机TIM和相关化学物质。

项目成果

Treatment of Sulfur Mustard Corneal Injury by Augmenting the DNA Damage Response (DDR): A Novel Approach.

通过增强 DNA 损伤反应 (DDR) 治疗硫芥角膜损伤：一种新方法。

• DOI: 10.1124/jpet.123.001686
• 发表时间: 2024
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: Shalwitz,Robert;Day,Tovah;Ruehlmann,AnnaKotsakis;Julio,Lindsay;Gordon,Shellaina;Vandeuren,Adrianna;Nelson,Marian;Lyman,Megan;Kelly,Kyle;Altvater,Amber;Ondeck,Celinia;O'Brien,Sean;Hamilton,Tracey;Hanson,RyanL;Wayman,Kayla;Mi
• 通讯作者: Mi