Carbon Monoxide: Novel Opportunities for Therapy

描述(由申请人提供)： 脓毒症并发急性肺损伤(ALI)和多器官功能障碍综合征(MODS)的高发病率和高死亡率反映了现有诊断标记物和治疗方法的不足。我们的基础科学家和翻译/临床研究人员组成的多学科团队是血红素加氧酶-1(HO-1)/一氧化碳(CO)和炎症消解领域的领导者，他们高效地协同工作，朝着一个共同的目标努力：即。推动气态分子CO领域的发展，使我们能够将CO病毒保护的临床前发现转化为人类疾病。这种翻译PPG将使我们能够实现使用新型细胞保护分子CO治疗如ALI等可怕疾病的最终目标的三个主要目标：i)阐明新的生理和细胞机制(S)，通过该机制，当低生理剂量给药时，有毒分子可以提供强大的细胞保护；2)识别CO的新分子靶点，这些靶点本身可以成为ALI诊断和治疗方法开发的平台；i)提供关键的概念验证“ALI第一”研究，为我们在下一个翻译PPG计划第二周期在ALI进行CO干预试验做准备。这三个主要目标的实现将对重症监护疾病和肺病社区产生重大影响，因为我们希望揭开ALI新的诊断生物标记物和/或治疗(S)。我们将尝试通过以下项目和核心来实现我们的目标：1.败血症和肺损伤中一氧化碳的细胞保护作用2.败血症所致肺损伤中一氧化碳和线粒体的质量控制3.一氧化碳对间充质基质细胞的调节4.一氧化碳和专门的促分解介质核心：核心A：行政核心B：临床研究协调核心C：脂质调节代谢核心D：败血症和急性肺损伤中的一氧化碳递送 (摘要结束)

DESCRIPTION (provided by applicant): 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 (End of Abstract)