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，并包括一个模型 暴露在发泡剂化学物质中造成的眼组织损伤。尤其是，我们将重点关注后 翻译性组蛋白修饰是由于接触起泡剂刘易斯特引起的，这是最常见的 强大的以砷为基础的化学战剂，暴露在这种物质中会对人体造成损害， 组织损伤(如肺部)和局部损伤(如眼睛表面)。卢很容易穿透衣服 和个人防护装备(PPE)，使受影响的人群特别容易引起 急性皮肤、肾脏和肺部损伤。因此，我们假设暴露于LEW的小鼠通过 皮下吸收、吸入或直接眼部接触会通过 溴域4(BRD4)介导组蛋白超乙酰化和促炎反应的机制 砷的原型的发展准确地模拟卢诱导的分子发病机制 Eyes将极大地促进制定新的应对措施。在目标1中，我们建议 研究小鼠皮肤暴露于路易斯特是否会引发眼组织损伤，并确定 眼组织病理生物学中涉及的分子途径。在目标2中，我们将确定直视 LEW暴露通过组蛋白修饰和基因改变导致小鼠眼组织损伤 表情。在目标#3中，我们确定了小鼠眼睛直接暴露于氧化苯砷(PAO)是否会导致 眼组织损伤类似于LEW诱导的眼损伤。我们假设鲍尔，一种毒性相对较小的 刘易斯类似物，模拟卢诱导的眼睛发病机制，因此，它是否可以用于 验证新设计的针对BRD4的解毒剂，以对抗卢诱导的损伤。我们将重点关注角膜 以及通过组织学和分子评估的视网膜组织损伤。这些数据将为第一次 时间--砷引起眼损伤的细胞和分子机制。这项研究还将 建立治疗平台，克服目前测试化学战剂的技术困难 用于实验室环境中的眼睛研究，以验证新设计的对抗措施。我的研究 专业知识在于视网膜变性领域，这是对该项目中拟议的调查的补充。

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.