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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL108801-04
Application #
8702217
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Harabin, Andrea L
Project Start
2011-08-15
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Ma, Kevin C; Schenck, Edward J; Pabon, Maria A et al. (2018) The Role of Danger Signals in the Pathogenesis and Perpetuation of Critical Illness. Am J Respir Crit Care Med 197:300-309
Schenck, Edward J; Oromendia, Clara; Torres, Lisa K et al. (2018) Rapidly Improving ARDS in Therapeutic Randomized Controlled Trials. Chest :
Schenck, Edward J; Ma, Kevin C; Murthy, Santosh B et al. (2018) Danger Signals in the ICU. Crit Care Med 46:791-798
Ghanta, Sailaja; Kwon, Min-Young; Rosas, Ivan O et al. (2018) Mesenchymal Stromal Cell Therapy: Does the Source Matter? Crit Care Med 46:343-345
Baron, Rebecca M; Kwon, Min-Young; Castano, Ana P et al. (2018) Frontline Science: Targeted expression of a dominant-negative high mobility group A1 transgene improves outcome in sepsis. J Leukoc Biol 104:677-689
Shu, Chang; Huang, He; Xu, Ying et al. (2018) Pressure Overload in Mice With Haploinsufficiency of Striated Preferentially Expressed Gene Leads to Decompensated Heart Failure. Front Physiol 9:863
Harrington, John S; Schenck, Edward J; Oromendia, Clara et al. (2018) Acute respiratory distress syndrome without identifiable risk factors: A secondary analysis of the ARDS network trials. J Crit Care 47:49-54
Siempos, Ilias I; Ma, Kevin C; Imamura, Mitsuru et al. (2018) RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury. JCI Insight 3:
Rosas, Ivan O; Goldberg, Hilary J; Collard, Harold R et al. (2018) A Phase II Clinical Trial of Low-Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis. Chest 153:94-104
Chen, Xi; Wang, Shaojun; Xu, Haiwei et al. (2017) Evidence for a retinal progenitor cell in the postnatal and adult mouse. Stem Cell Res 23:20-32

Showing the most recent 10 out of 85 publications