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

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.

在本行政补充文件中，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起泡剂化学物质引起的眼组织损伤。特别是，我们将重点关注后期翻译组蛋白修饰是由于暴露于起泡剂路易氏剂而引起的，这是最常见的起泡剂之一。强效砷基化学战剂，接触该剂会对人体造成全身性损害组织损伤（例如肺部）和局部损伤（例如眼睛表面）。 LEW 很容易渗透衣服和个人防护装备（PPE），使暴露人群特别容易造成急性皮肤、肾脏和肺部损伤。因此，我们假设小鼠通过以下方式暴露于 LEW：皮下吸收、吸入或直接眼睛接触会通过眼睛造成眼组织损伤溴结构域 4 (BRD4) 介导的组蛋白过度乙酰化和促炎反应的机制，以及准确模仿 LEW 诱导的分子发病机制的砷原型的开发眼睛将极大地促进新的反制措施的制定。在目标#1中，我们建议研究小鼠皮肤暴露于路易氏剂是否会引发眼组织损伤并确定其原因参与眼组织病理学的分子途径。在目标#2中，我们将确定是否直视小鼠暴露于 Lew 会通过组蛋白修饰和基因改变导致眼组织损伤表达。在目标#3中，我们确定小鼠眼睛直接接触氧化苯胂 (PAO) 是否会导致眼组织损伤类似于 LEW 引起的眼损伤。我们假设PAO是一种毒性相对较小的物质 Lewisite 类似物，模拟 LEW 诱导的眼部发病机制，因此，它是否可用于验证新设计的针对 BRD4 的解毒剂，以对抗 LEW 引起的损伤。我们将重点关注角膜通过组织学和分子评估评估视网膜组织损伤。这些数据将首次建立负责砷介导的眼损伤的细胞和分子机制的时间。该研究还将建立治疗平台并克服当前测试化学战剂的技术困难用于实验室环境中的眼部研究，以验证新设计的对抗措施。我的研究视网膜变性领域的专业知识补充了该项目中拟议的调查。