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

在这份行政补充文件中，我们建议扩大眼部疾病的动物模型， 眼部组织因暴露于化学起泡剂而受损特别是，我们将重点放在后- 翻译组蛋白修饰导致暴露于起泡剂路易氏剂，这是一个最重要的 强有力的砷基化学战剂，暴露于这种化学战剂会损害人体的全身 组织损伤（例如，肺）和局部损伤（例如，眼睛的表面）。LEW很容易穿透衣服 和个人防护装备（PPE），使暴露的人群特别容易受到影响，导致 急性皮肤、肾脏和肺部损伤。因此，我们假设暴露于LEW的小鼠， 皮下吸收、吸入或直接眼部接触，通过 布罗莫结构域4（BRD 4）介导的组蛋白超乙酰化和促炎反应的机制，以及 砷原型的发展准确地模仿LEW诱导的分子发病机制， 眼睛将大大促进新的对抗措施的发展。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 参与眼组织病理学的分子途径。在aim#2中，我们将确定是否直视 小鼠暴露于Lew通过组蛋白修饰和基因改变引起眼组织损伤 表情在目标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诱导的眼损伤。我们假设，PAO，一种毒性相对较小的 路易氏剂类似物，模拟LEW诱导的眼部发病机制，因此，它是否可以用于 验证新设计的针对BRD 4的解毒剂，以对抗LEW诱导的损伤。我们将重点关注角膜 以及视网膜组织损伤的组织学和分子生物学评估。这些数据将首次建立 时间砷介导的眼损伤的细胞和分子机制负责。该研究还将 建立一个治疗平台，克服目前在测试化学战剂方面的技术困难， 在实验室环境中进行眼科研究，以验证新设计的对抗措施。我的研究 专家在视网膜变性领域的专长，补充了本项目的拟议调查。

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.