PROJECT SUMIVIARY (See Instructions); The goal of this Translational Program Project Grant is to advance the biologic understanding and therapeutic application of inhaled carbon monoxide (CO) in sepsis-induced ALI. Core B (the Clinical Studies Coordination Core) will provide important resources and support for the Project Investigators in carrying out the proposed Translational Studies. Specifically, this core will provide human samples from well-phenotyped subjects to investigators in Projects 1-4 and serve as the Data Coordinating Center (DCC) for the Phase I safety and proof-of-concept trials in administering inhaled CO to patients with sepsis-induced ALI. Objective 1: To identify patients with the systemic inflammatory response syndrome (SIRS), sepsis, and sepsis-induced acute lung injury (ALI);to collect and store plasma, RNA, and primary cells from subjects in a clinical biorepository;and to provide biostatistical support for Projects 1-4 for the analysis and interpretation of studies performed using these specimens. This Core will provide investigators in Projects 1-4 with uniformly processed clinical samples from well-characterized critically ill patients from the BWH Medical ICU. We anticipate that we will enroll at least 1,000 subjects (over 5 years). Objective 2: To serve as the DCC for the Phase 1 first-in-ALI safety study for inhaled CO in sepsis induced ALI in Project 1 and proof-of-concept study with collection of muscle biopsies after inhaled CO in Project 2. Collection of samples as in Objective 1 will be undertaken pre- and post-CO exposure for distribution to the investigators in Projects 1-4. As the DCC for the clinical trials in Years 3-5, we will provide support to the investigators at BWH, MGH, and DUMC in carrying out these trials. In years 1-2, we will submit the IND and IRB applications and develop the infrastructure for initiating the trials. Once the trial is initiated, we will manage the database, process adverse events, and produce regular reports to the DSMB, FDA, and investigators. We will also collect and analyze data from Project investigators regarding levels of biomarkers in clinical samples. Overall Objective: By centralizing clinical trials oversight, clinical sample collection, and phenotyping by experienced and expert investigators, well-characterized and uniformly processed clinical samples can be provided to investigators from Projects 1-4 to facilitate their translational research aims. Importantly, data from the Phase I safety and proof-of-concept studies will form the basis for a Phase ll/lll clinical trial in the 2nd 5-year cycle of this translational Program Project Grant.

Public Health Relevance

Sepsis-induced ALI is a condition with high morbidity and mortality and with limited available treatment options. This Translational Program Project Grant proposes to advance the understanding and application of a novel therapeutic modality, inhaled carbon monoxide, in these critically ill patients. This Core will play a key role in facilitating the translational aspects of this proposal for all of the proposed projects.

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)
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Brigham and Women's Hospital
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Beitler, Jeremy R; Schoenfeld, David A; Thompson, B Taylor (2014) Preventing ARDS: progress, promise, and pitfalls. Chest 146:1102-13
Siempos, Ilias I; Lam, Hilaire C; Ding, Yan et al. (2014) Cecal ligation and puncture-induced sepsis as a model to study autophagy in mice. J Vis Exp :e51066
Suliman, Hagir B; Piantadosi, Claude A (2014) Mitochondrial biogenesis: regulation by endogenous gases during inflammation and organ stress. Curr Pharm Des 20:5653-62
Agrawal, Pankaj B; Pierson, Christopher R; Joshi, Mugdha et al. (2014) SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy. Am J Hum Genet 95:218-26
Nakahira, Kiichi; Cloonan, Suzanne M; Mizumura, Kenji et al. (2014) Autophagy: a crucial moderator of redox balance, inflammation, and apoptosis in lung disease. Antioxid Redox Signal 20:474-94
Schumacker, Paul T; Gillespie, Mark N; Nakahira, Kiichi et al. (2014) Mitochondria in lung biology and pathology: more than just a powerhouse. Am J Physiol Lung Cell Mol Physiol 306:L962-74
Colas, Romain A; Shinohara, Masakazu; Dalli, Jesmond et al. (2014) Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. Am J Physiol Cell Physiol 307:C39-54
Shinohara, Masakazu; Kibi, Megumi; Riley, Ian R et al. (2014) Cell-cell interactions and bronchoconstrictor eicosanoid reduction with inhaled carbon monoxide and resolvin D1. Am J Physiol Lung Cell Mol Physiol 307:L746-57
Ryter, Stefan W; Koo, Ja Kun; Choi, Augustine M K (2014) Molecular regulation of autophagy and its implications for metabolic diseases. Curr Opin Clin Nutr Metab Care 17:329-37
Kraft, Bryan D; Piantadosi, Claude A; Benjamin, Ashlee M et al. (2014) Development of a novel preclinical model of pneumococcal pneumonia in nonhuman primates. Am J Respir Cell Mol Biol 50:995-1004

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