The high morbidity and mortality of acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS) in sepsis reflect the inefficacy of currently available diagnostic markers and therapeutic modalities. Our multi-disciplinary team of basic scientists and translational/clinical researchers are leaders in the field of heme oxygenase-1 (HO-1 )/carbon monoxide (CO) and resolution of inflammation who have worked efficiently and synergistically towards a common goal: that is. to advance the field of gaseous molecule CO so that we can translate the pre-clinical findings of CO cvtoprotection to human disease. This translational PPG will enable us to accomplish three major goals in our ultimate quest to use a novel cytoprotective molecule, CO, in the treatment of a dreadful disease such as ALI: i) elucidate novel physiologic and cellular mechanism(s) by which a toxic molecule when administered at low physiologic doses can provide potent cytoprotection ii) identify novel molecular targets of CO which can by themselves be a platform for the development of both diagnostic and therapeutic modalities in ALI Hi) provide critical proof-of-concept "first in ALI" studies to prepare us for a CO intervention trial in ALI at the next Cycle II of the translational PPG program. The impact of reaching these 3 major goals will be significant in the critical care illness and pulmonary community as we hope to unravel new diagnostic biomarkers and/or treatment(s) for ALI. We will attempt to reach our goals by the addressing the following projects and cores: Projects: 1. Cytoprotection by Carbon Monoxide in Sepsis and Lung Injury 2. Carbon Monoxide and Mitochondrial Quality Control in Sepsis-induced Lung Injury 3. Mesenchymal Stromal Cell Conditioning by Carbon Monoxide 4. Carbon Monoxide and Specialized Pro-Resolving Mediators Cores: Core A: Administrative Core Core B: Clinical Studies Coordination Core Core C: Lipid Mediator Metabolomics Core D: Carbon Monoxide Delivery in Sepsis and Acute Lung Injury

Public Health Relevance

For this Cycle I of RFA PAR-09-185: Translational Programs in Lung Diseases (P01), each project will integrate basic aims to determine novel mechanism(s) by which CO mediates its cytoprotection with translational aims focused on proof-of-concept non human primate and human studies. The synergism between the projects and cores will provide the groundwork to conduct Phasell/lll inhaled CO intervention trial in ALI at the next Cycle II of this translational P01 application.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1-PPG-A (M1))
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Harabin, Andrea L
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Brigham and Women's Hospital
United States
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