Post-translational histone modification in ocular tissues of mice exposed to arsenicals

砷暴露小鼠眼组织的翻译后组蛋白修饰

基本信息

批准号：
10175917
负责人：
Marina Gorbatyuk
金额：
$ 12.45万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10175917
关键词：
Acetylation Acute Administrative Supplement Affect Anatomy Animal Model Animals Anterior Antidotes Area Arsenic Arsenicals Blindness Blood Circulation Blood Vessels Bromodomain Bulla Chemical Warfare Agents Chemicals Clothing Complement Cornea Cutaneous DNA Data Development Disease Dose Epithelial Cells Equipment Evaluation Event Exposure to Eye Eye Injuries Gene Expression Gene Expression Profile Hazardous Substances Histology Histones Human Human body Inflammation Inflammatory Inflammatory Response Inhalation Injury Injury to Kidney Investigation Kidney Laboratories Location Lung Measures Mediating Methods Modeling Molecular Mus Mustard Gas Organ Oxides Pain Parents Pathogenesis Pathologic Pathway interactions Penetration Plasma Poison Publishing Research Retina Retinal Degeneration Route Scientist Skin Skin injury Structure Surface Swelling Symptoms Testing Therapeutic Thick Time Tissues Toxic effect Vesicants absorption analog anterior chamber base corneal epithelium design disease registry experience exposed human population eye chamber fighting histone modification irritation lewisite lung injury posterior eyeball chamber protein H(3)prototype subcutaneous tissue injury

Acetylation Acute Administrative Supplement Affect Anatomy Animal Model Animals Anterior Antidotes Area Arsenic Arsenicals Blindness Blood Circulation Blood Vessels Bromodomain Bulla Chemical Warfare Agents Chemicals Clothing Complement Cornea Cutaneous DNA Data Development Disease Dose Epithelial Cells Equipment Evaluation Event Exposure to Eye Eye Injuries Gene Expression Gene Expression Profile Hazardous Substances Histology Histones Human Human body Inflammation Inflammatory Inflammatory Response Inhalation Injury Injury to Kidney Investigation Kidney Laboratories Location Lung Measures Mediating Methods Modeling Molecular Mus Mustard Gas Organ Oxides Pain Parents Pathogenesis Pathologic Pathway interactions Penetration Plasma Poison Publishing Research Retina Retinal Degeneration Route Scientist Skin Skin injury Structure Surface Swelling Symptoms Testing Therapeutic Thick Time Tissues Toxic effect Vesicants absorption analog anterior chamber base corneal epithelium design disease registry experience exposed human population eye chamber fighting histone modification irritation lewisite lung injury posterior eyeball chamber protein H(3)prototype subcutaneous tissue injury

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项目摘要

In this administrative supplement, we propose to expand animal models of ocular diseases and include a model of ocular tissue damage caused by exposure to vesicant chemicals. In particular, we will focus on post- translational histone modifications resulted from exposure to the blister agent Lewisite that is one of the most powerful arsenic-based chemical warfare agents, exposure to which damages the human body by both systemic tissue injury (e.g., to the lungs) and local injury (e.g., to the surface of the eye). LEW easily penetrates clothing and personal protective equipment (PPE), making the exposed human population particular susceptible causing acute skin, kidney and lung injuries. Therefore, we hypothesize that mice exposed to LEW either through subcutaneous absorption, inhalation, or direct eye contact experience ocular tissue damage through the mechanism of bromodomain 4 (BRD4)-mediated histone hyperacetylation and pro-inflammatory response, and the development of arsenical prototypes accurately mimicking the LEW-induced molecular pathogenesis of the eye will significantly facilitate the development of new counteractive measures. In aim #1, we propose to investigate whether the cutaneous exposure of mice to Lewisite triggers ocular tissue damage and to identify the molecular pathways involved in ocular tissue pathobiology. In aim#2, we will determine whether direct eye exposure to Lew in mice causes ocular tissue damage through histone modification and altered gene expression. In aim#3, we determine whether direct eye exposure to phenylarsine oxide (PAO) in mice causes ocular tissue damage similar to LEW-induced ocular injury. We hypothesize that PAO, a relatively less toxic Lewisite analog, mimics LEW-induced ocular pathogenesis and, therefore, whether it could be used to validate newly designed antidotes targeting BRD4 to fight LEW-induced damage. We will focus on corneal and retinal tissue damage through histology and molecular assessment. These data will establish for the first time the cellular and molecular mechanisms responsible for arsenic-mediated ocular injury. The study will also generate a therapeutic platform and overcome current technical difficulties in testing chemical warfare agents for eye research in a laboratory setting to validate newly designed counteract measures. My research expertise lies in the area of retinal degeneration which complements the proposed investigation in this project.

在这种行政补充中，我们建议扩大眼部疾病的动物模型，并包括一个模型暴露于囊泡化学物质引起的眼组织损伤。特别是，我们将专注于职位翻译组蛋白的修饰是由于暴露于泡沫剂刘易斯石而导致的，这是最多的。强大的基于砷的化学战剂，暴露于两种全身性的人体损害人体组织损伤（例如，到肺部）和局部损伤（例如，眼睛表面）。 Lew轻松穿透衣服和个人防护设备（PPE），使暴露的人口特别敏感急性皮肤，肾脏和肺部受伤。因此，我们假设小鼠通过皮下吸收，吸入或直接眼接触经历眼组织通过溴结构域4（BRD4）介导的组蛋白高乙酰化和促炎反应的机理，以及砷原型的发展准确地模仿了LEW诱导的分子发病机理眼睛将显着促进新的反活性措施的发展。在AIM＃1中，我们建议调查小鼠对路易斯特岩的皮肤暴露是否会触发眼组织损害，并确定参与眼组织病理生物学的分子途径。在AIM＃2中，我们将确定是否直接眼睛小鼠暴露于LEW会通过组蛋白修饰和改变基因引起眼组织损伤表达。在AIM＃3中，我们确定小鼠导致苯烷氧化物（PAO）的直接暴露眼组织损伤类似于LEW诱导的眼部损伤。我们假设PAO是一种相对较小的毒性路易斯特类似物，模仿LEW诱导的眼发病机理，因此，是否可以使用它验证针对BRD4的新设计的解毒剂来对抗LEW诱导的损坏。我们将专注于角膜通过组织学和分子评估通过视网膜组织损害。这些数据将建立第一个数据时间，导致砷介导的眼部损伤的细胞和分子机制。这项研究也将产生一个治疗平台并克服当前的技术困难测试化学战代理用于实验室环境中的眼睛研究，以验证新设计的抵消措施。我的研究专业知识在于视网膜变性领域，它补充了该项目中提议的调查。