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Your Environment. Your Health.

EXTRACELLULAR RNA AS THERAPEUTIC TARGET AFTER TOXIC CHEMICAL INHALATION

Export to Word (http://www.niehs.nih.gov//portfolio/index.cfm/portfolio/grantdetail/grant_number/U01ES025069/format/word)
Principal Investigator: Ahmad, Aftab
Institute Receiving Award University Of Alabama At Birmingham
Location Birmingham, AL
Grant Number U01ES025069
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 11 Dec 2014 to 31 May 2021
DESCRIPTION (provided by applicant): : Exposure to toxic inhaled chemicals like sulfur mustard (SM) can cause injuries to the respiratory system, eyes, skin and also frequently leads to death. The pathogenesis of sulfur mustard-induced injury is incompletely understood and a search for effective treatment regimens has been a challenge. SM-induced toxicities activate several pathways that include the coagulation and inflammatory pathways. Extracellular RNA (exRNA) and hypoxic signaling events drive several factors implicated in these pathways. This proposal focuses on understanding the role of extracellular RNA and associated inflammatory pathways in SM-induced injuries. These studies will be carried out using CEES, a surrogate of sulfur mustard as well as sulfur mustard. We hypothesize that CEES/SM exposures release exRNA that causes activation of the coagulation pathway and also inhibition of HIFs that in turn activate proinflammatory pathways. And that blocking of exRNA and stabilization of HIFs can alleviate toxicity and lung injury. The proposed studies are divided into three aims. Aim 1 will test whether blockage of exRNA using RNase or synthetic cationic polymers can mitigate CEES/SM-induced injury. The second aim will test whether activation of the hypoxia- inducible transcription factor will decrease inflammation and mitigate CEES-induced injury. Aim 3 will determine mechanisms by which CEES causes injury. This aim will also test whether therapeutic inhibition of exRNA from other chemical inhalations like chlorine can reduce injury. Since previous studies from our group and others have indicated a beneficial effect with combination therapies this aim will also test whether combining the two therapies tested in Aims 1 and 2 above can provide a better protection. Results of the proposed research will help identify treatment options for sulfur mustard exposures as well as other potentially toxic chemical inhalations associated with increased exRNA and metabolic poisoning.
Science Code(s)/Area of Science(s) Primary: 37 - Counter-Terrorism
Publications See publications associated with this Grant.
Program Officer Srikanth Nadadur
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