Unraveling the corneal and retinal mechanisms of chemical injury

揭示化学损伤的角膜和视网膜机制

基本信息

批准号：
10882069
负责人：
ROYCE MOHAN
金额：
$ 49.82万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10882069
关键词：
Achievement Acute Alkalies Anterior Applications Grants Arginine deiminase Automobile Driving Binding Blindness Calcium Cell Culture Techniques Cell Death Characteristics Chemical Exposure Chemical Injury Chronic Cicatrix Clinic Clinical Cornea Corneal Ulcer Corneal pain Cutaneous DNA Damage Data Disease Dose Drug Combinations Drug Targeting Enzymes Epithelial Cells Event Evolution Exposure to Eye Eye Injuries Eye diseases Fibrosis Funding Future Genetic Gliosis Grant Human In Vitro Infection prevention Inflammation Injury Intermediate Filament Proteins Investigation Knockout Mice Laser injury Link Mechlorethamine Mediating Mediator Medical Modeling Modification Molecular Muller&apos s cell Mus Mustard Gas Ocular Pathology Oryctolagus cuniculus Oxides Pathologic Pathology Pathway interactions Pharmaceutical Preparations Poison Post-Translational Protein Processing Protein Isoforms Proteins Proteomics Publishing Rattus Reporting Research Retina Retinal Degeneration Security Severities Sulfur System TP53 gene Testing Therapeutic Tissues Translating Vesicants Visual impairment analog biological adaptation to stress cellular targeting chemical countermeasure chemical threat combat corneal epithelium crosslink drug discovery experimental study human disease in vivo in vivo Model inhibitor injured lewisite lung injury mass casualty novel pharmacologic programs response symptom management weapons

项目摘要

Abstract: Chemical threat agents can potentially be weaponized to cause mass casualties and such egregious events are of grave concern to homeland security. Sulfur mustard and its analog nitrogen mustard (NM) are vesicants that cause severe acute injury to ocular tissues and ultimately develop fibrotic scarring leading to vision loss. As medical treatments for vesicant injury have yet to be developed for paucity of a complete understanding of their pathophysiological mechanisms, this unmet medical need remains an urgent matter of importance to the Chemical Countermeasures Research Program (CCRP). Under an exploratory R21 grant funded by the CCRP, we have discovered that NM injury to the mouse cornea triggers a rapid and profound induction of retinal gliosis. This retinal response is coordinated in reactive Muller glia with activation of the posttranslational modification (PTM) known as citrullination. This finding extends our prior results showing that retinal hypercitrullination driven by the enzyme peptidyl arginine deiminase (PAD)-4 is a shared pathological feature that is common to a number of different injury and disease paradigms. But critical gaps remain regarding the molecular steps involved in the PAD-hypercitrullination axis. As other published reports have shown that NM crosslinks tumor suppressor p53 and the p53 DNA damage pathway interacts with PAD4, these data provokes an interesting idea whether these two major orchestrators of pathological response are tied to activating hypercitrullination in both the cornea and retina. In this R01 grant proposal, we will investigate the acute and chronic (delayed) injury mechanisms of NM across the cornea and retina in mouse and rat models. Specifically in Aim 1, we will investigate the molecular mechanisms of the p53-PAD axis involving corneal hypercitrullination and identify the relevant PAD using both in vivo and cell culture models to study NM injury. In Aim 2, we will characterize the corneal and retinal citrullinomes of NM injury using proteomics by examining the temporal changes over the early and chronic stages. This study will allow us to identify key PAD substrates of acute and chronic injury states, permitting us to decipher the evolution of key protein players modified by citrullination in perpetuating corneal and retinal pathology. We believe this in-depth investigation into hypercitrullination in the NM injured eye could unravel novel mechanisms and druggable PAD targets that would be critical for drug discovery to combat chemical injury to the human eye. Given that PADs are already being investigated as targets for several common diseases, the likelihood of clinical drugs becoming available for humans in the near future makes this an attractive target class for further mechanistic assessment.

抽象的：化学威胁代理可能会被武器造成大规模伤亡等重视事件引起了国土安全的严重关注。硫芥末酱及其类似物氮芥末（NM）是对眼组织严重急性损伤和最终会产生纤维化疤痕，从而导致视力丧失。作为囊泡损伤的医疗治疗尚未为完全理解其病理生理学而开发机制，这种未满足的医疗需求仍然是对化学物质的重要问题对策研究计划（CCRP）。根据探索性R21赠款 CCRP，我们发现NM对小鼠角膜的损伤触发了快速而深刻的诱导视网膜神经胶质病。这种视网膜反应在反应性muller Glia中与翻译后修饰（PTM）的激活称为柠檬化。这一发现扩展了我们先前的结果表明，由肽基精氨酸驱动的视网膜高乳硫酸化脱氨酶（PAD）-4是一种共同的病理特征，多种损伤常见和疾病范例。但是关于涉及的分子步骤仍然存在关键差距垫子尿液轴。正如其他已发表的报告表明NM交联肿瘤抑制器p53和p53 DNA损伤途径与PAD4相互作用，这些数据引起了有趣的想法是否将病理反应的两个主要编排与激活角膜和视网膜中的过度乳腺癌。在此R01赠款建议中，我们将研究NM跨角膜和视网膜的急性和慢性（延迟）损伤机制在鼠标和大鼠模型中。特别是在AIM 1中，我们将研究分子机制涉及角膜过度乳腺素的p53-pad轴，并使用这两者在体内和细胞培养模型研究NM损伤。在AIM 2中，我们将表征角膜和使用蛋白质组学的NM损伤的视网膜柑橘类别，通过检查临时变化早期和慢性阶段。这项研究将使我们能够识别急性和慢性损伤状态，使我们能够破译由关键蛋白玩家的演变。柠檬化在永久性角膜和视网膜病理学中。我们相信这项深入的调查在NM受伤的眼睛中进行过度乳腺素化可能会揭开新颖的机制和可药用的垫子对药物发现至关重要的靶标，要对人眼抵抗化学损伤。给出该垫已经被研究为几种常见疾病的目标，可能性在不久的将来可以为人类使用的临床药物使这是一个有吸引力的目标课程进行进一步的机械评估。