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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES034490&format=word)
| Principal Investigator: Leikauf, George Douglas | |
|---|---|
| Institute Receiving Award | University Of Cincinnati |
| Location | Cincinnati, OH |
| Grant Number | R01ES034490 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 20 Aug 2023 to 31 Jul 2026 |
| DESCRIPTION (provided by applicant): | Project Summary The overall goal of this application is to determine the sequence of key events that leads to the pathological progression elicited after acrolein and phosgene inhalation. Chemically-induced acute lung injury (CIALI) is a form of acute respiratory distress syndrome (ARDS). ARDS is characterized by loss of alveolar barrier function that leads to increased protein and neutrophil infiltration into the alveolar air space. Currently, ARDS therapy is mainly limited to managed mechanical ventilation, and the mortality rate remains high. Mortality is influenced by sex, age, and genetic susceptibility in patients, which can be experimentally modeled in mice. A major CIALI risk factor is smoke inhalation and the main irritant in smoke is acrolein. Death can be immediate or delayed resulting from a complex cellular and pulmonary responses that progress with time and dictate the severity of the injury. Another chemical that can induce delayed pulmonary edema is phosgene, which was develop as a chemical weapon in World War I. Currently, it is unknown whether acrolein and phosgene produce CIALI by the same overlapping mechanisms or by mechanisms unique to each chemical. To develop effective therapeutic interventions, more studies are needed to understand the disease-progression and injury-resolution mechanisms underlying severity of injury and mortality. This proposal has the following Specific Aims: 1. Determine the temporal events of sensitivity and resistance to acrolein-induced acute lung injury, 2. Delineate critical pathways in acrolein-induced CIALI progression and resolution using multiomic analyses, and 3. Compare and contrast the progression of phosgene-induced CIALI to that of acrolein-induced CIALI. Detailed time course analyses will evaluate bronchoalveolar lavage, lung histopathology, spatial lipidomics, spatial metabolomics and single-cell and spatial transcriptomics following acrolein or phosgene exposure. Strain- and sex-specific responses will be investigated. Determining the sequence of key pathological events controlling the progression and resolution of acute lung injury elicited by acrolein and phosgene should provide a mechanistic basis for the development of therapy. |
| Science Code(s)/Area of Science(s) |
Primary: 37 - Counter-Terrorism Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | No publications associated with this grant |
| Program Officer | Srikanth Nadadur |