Hydrogen sulfide toxicity to the cornea

硫化氢对角膜的毒性

基本信息

批准号：
10459289
负责人：
Rajiv Ravindra Mohan
金额：
$ 19.45万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459289
关键词：
Acute Anatomy Animals Anterior eyeball segment structure Antidotes Australia Automobile Driving Basic Science Blindness Brain Injuries Bulla Cardiac Cause of Death Cessation of life Chemical Weapons Chemicals Clinical Complex Cornea Corneal Injury Data Development Diagnostic Imaging Dose Drops Environmental Pollutants Enzyme-Linked Immunosorbent Assay Etiology Exposure to Eye Eye Development Eyelid structure Fibroblasts Fibrosis Fill-It Film Fluorescein Gases Goals Health Hazards Heart Histologic Home Human Hydrogen Sulfide Imaging Device Immunofluorescence Immunologic In Vitro Industrialization Inflammation Inflammatory Injury Intervention Intoxication Ions Iraq Knowledge Lacrimation Lead Lung Membrane Potentials Methods Microscope Mitochondria Modeling Molecular Molecular Target Neurologic Ophthalmic examination and evaluation Ophthalmologist Oryctolagus cuniculus Outcome Oxidative Stress Pathway interactions Persons Phase-Contrast Microscopy Pre-Clinical Model Process Publishing Quantitative Reverse Transcriptase PCR Reactive Oxygen Species Research Research Personnel Sewage Sodium Symptoms TdT-Mediated dUTP Nick End Labeling Assay Techniques Terrorism Testing Time Tissues Toxic effect Transmission Electron Microscopy Ulcer Western Blotting World War I acute toxicity base conjunctiva cytochrome c oxidase efficacious treatment experience human model in vitro Model in vivo in vivo Model irritation medical countermeasure mitochondrial membrane new therapeutic target novel ocular surface pre-clinical prevent respiratory therapeutic target tomography tonometry

项目摘要

ABSTRACT Hydrogen sulfide (H2S) is a toxic gas, chemical weapon, environmental pollutant, and its intoxication is the second most common cause of death in industrial states. The use of H2S by terrorists to harm innocent people and cause mass causalities is an imminent threat as it can be prepared easily with common chemicals in a home setting. In humans, H2S intoxication causes neurological, respiratory, cardiac, ocular complications, and death. In the eye, H2S exposure causes corneal inflammation and fibrosis/opacity that leads to vision loss. The lack of mechanistic understanding driving H2S toxicity in the cornea and unavailability of suitable human in vitro and animal in vivo preclinical models are primary factors for lack of safe and efficacious therapies to minimize and mitigate H2S toxicity in the cornea. The main goal of this proposal is to determine the molecular mechanisms of H2S induced acute corneal toxicity and identify novel therapeutic targets to mitigate H2S toxicity in the cornea using in vitro and in vivo models. Our central hypothesis is that H2S, on contact to the eye, reacts with tears and generates highly reactive/toxic ions, compromises the mitochondrial function of the corneal stromal fibroblasts, and causes oxidative stress and fibrosis/opacity in the cornea and finally, vision loss. Two specific aims will test this. Aim-1 will define the dose- and time-dependent H2S toxicity to the cornea in vivo using rabbits. Aim 2 will delineate molecular and cellular mechanisms of H2S-induced acute toxicity to the cornea using the in vitro model of human corneal stromal fibroblasts and in vivo using rabbit corneas. Various clinical eye exam and imaging tools, cellular and molecular techniques will be used to accomplish these aims. The successful completion of the project will have a significant impact in the field as it fills gaps in the molecular mechanisms and pathways and potential novel targets for the intervention of H2S induced corneal damage and blindness. The long-range goal of this project is to develop an effective and safe medical countermeasure to prevent/treat vision loss from H2S exposure.

抽象的硫化氢（H2S）是一种有毒气体，化学武器，环境污染物，其中毒是工业州第二大最常见的死亡原因。恐怖分子使用H2来伤害无辜者并导致质量因果关系是迫在眉睫的威胁，因为它可以在家庭环境。在人类中，H2S中毒会导致神经，呼吸道，心脏，眼并发症，并且死亡。在眼中，H2S暴露会导致角膜炎症和纤维化/不透明，从而导致视力丧失。缺乏理解驱动H2S毒性在角膜中的毒性的理解，而在体内体内临床前模型是缺乏安全有效疗法的主要因素最小化和减轻角膜中H2S的毒性。该提议的主要目标是确定分子 H2S的机制诱导急性角膜毒性并识别新的治疗靶标，以降低H2S毒性在角膜中使用体外和体内模型。我们的中心假设是，H2S接触到眼睛，泪水反应并产生高反应性/有毒离子，损害了该线粒体功能角膜基质成纤维细胞，并在角膜中引起氧化应激和纤维化/不透明度，最后是视力损失。两个具体的目标将测试这一点。 AIM-1将定义剂量和时间依赖于角膜的H2S毒性在体内使用兔子。 AIM 2将描绘H2S诱导的急性毒性的分子和细胞机制使用人角膜基质成纤维细胞和体内使用兔角膜的体外模型的角膜。各种临床眼科检查和成像工具，细胞和分子技术将用于完成这些目标。该项目的成功完成将对该领域产生重大影响，因为它填补了空白 H2S诱导的分子机制，途径以及潜在的新目标角膜伤害和失明。该项目的远程目标是开发有效且安全的医疗防止/治疗H2S暴露视力丧失的对策。