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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.

摘要