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.
In this administrative supplement, we propose to investigate whether mice exposed to lewisite either through subcutaneous absorption or direct eye contact experience ocular tissue damage and to determine molecules responsible for ocular tissue pathobiology.
|Starr, Christopher R; Pitale, Priyamvada M; Gorbatyuk, Marina (2018) Translational attenuation and retinal degeneration in mice with an active integrated stress response. Cell Death Dis 9:484|