Sepsis and the benefits of permissive hypoxia

脓毒症和允许性缺氧的好处

• 批准号: 10224259
• 负责人: Shahzad Shaefi
• 金额: $ 19.39万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224259
• 关键词: Acute; Adenosine; Adenosine Triphosphate; Admixture; Affect; Animal Model; Antiinflammatory Effect; Attention; Bacterial Model; Biliverdine; Binding; Bioenergetics; Biological; Biological Process; Biology; Carbon Monoxide; Caring; Cell Death; Cell Hypoxia; Cell physiology; Cells; Cessation of life; Clinical; Critical Care; Critical Illness; Data; Development Plans; Disease; Ensure; Environment; Equilibrium; Exposure to; Free Radicals; Functional disorder; Funding; Gases; General Anesthesia; Generations; Goals; Health; Heme; Hemeproteins; Hospitals; Hyperoxia; Hypoxemia; Hypoxia; Hypoxia Pathway; Immune response; Impairment; Inflammation; Injury; Innate Immune Response; Intensive Care Units; Intervention; Intuition; Investigation; Iron; Lead; Link; Mediating; Mentorship; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Modernization; Morbidity - disease rate; Mus; Operating Rooms; Oxidative Stress; Oxygen; Oxygen Therapy Care; Palate; Patients; Perioperative Care; Pharmaceutical Preparations; Play; Positioning Attribute; Process; Production; Program Development; Protein Glycosylation; Reactive Oxygen Species; Recovery; Research; Resolution; Role; Scientist; Sepsis; Site; Structure; Supplementation; Tissues; Titrations; Transcend; United States; Up-Regulation; Work; biological adaptation to stress; career development; cecal ligation puncture; experience; gene product; glycosylation; health care delivery; heme oxygenase-1; improved outcome; innovation; insight; mitochondrial dysfunction; mortality; mouse model; neutrophil; normoxia; novel; polymicrobial sepsis; pre-clinical; protective effect; response; skills; stressor; supplemental oxygen

PROJECT SUMMARY / ABSTRACT This project proposes a five-year research career development program focused on the study of permissive hypoxia in sepsis to expand the depth and breadth of understanding of the underlying mechanisms of mitochondrial dysfunction in this milieu. Currently, oxygen administration is the most widely administered drug in in-hospital care, and is liberally titrated to avoid potentially injurious periods of hypoxemia. Mounting evidence in several allied species suggest that not only is hyperoxia detrimental, but that local tissue hypoxia may in fact be beneficial to an evolved, requisite, and protective biological process. In critical illness such as sepsis, mitochondrial dysfunction is common, due in large part to oxidative stress, that results in impaired ATP generation, mitophagy, and in some cases, cell death. Strategies to mitigate or ameliorate this dysfunction and promote decreases in morbidity and mortality are therefore sought. Delivery of exogenously delivered carbon monoxide (CO) has stood out as a promising strategy because of its ability to simulate a protective hypoxic pathway. CO is generated endogenously by heme oxygenase-1 (HO-1) as part of the stress response. These molecules are potently salutary in models of sepsis and tissue hypoxia. Mechanistically, mitochondria are principal targets for these bioactive gases, with both oxygen and CO competing for binding to the large number of hemoproteins within the matrices. Using established models of bacterial sepsis in mice involving cecal ligation and puncture, this project will evaluate the role of HO-1/CO in mitigating mitochondrial dysfunction through modulation of inflammation. We will study the neutrophil where preliminary data suggest that these cells are influenced by CO. These models will be used to characterize the host response to sepsis and how oxygen titration affects mitochondrial function and survival. We will assess changes in mitochondrial function and protein glycosylation signatures linked to metabolsism known to be altered during hypoxia, investigate how mitochondria in the neutrophil are influenced by oxygen, and evaluate HO-1 and CO in promoting effective and appropriate bacterial clearance and resolution of inflammation. Guided by strong mentorship with significant expertise, this work has the opportunity to transcend observations around oxygen titration in the perioperative and critical care settings. Further, this project includes a well- structured and rigorous career development plan to build upon the candidates strong clinical and preclinical experience. Combined with an extraordinary environment and institutional support, the successful completion of the proposed project will provide the candidate with the skills and experience necessary to successfully compete for funding as an independent clinician scientist, with translational expertise in an innovative research niche.

项目概要/摘要 该项目提出了一个为期五年的研究职业发展计划，重点关注宽容的研究 脓毒症缺氧扩大了对脓毒症潜在机制理解的深度和广度 在这种环境下线粒体功能障碍。目前，吸氧是最广泛使用的药物 在医院护理中，并可自由滴定以避免低氧血症的潜在伤害期。安装 几个近缘物种的证据表明，高氧不仅有害，而且局部组织缺氧 事实上可能有利于进化的、必要的和保护性的生物过程。在危重疾病中，例如 脓毒症中，线粒体功能障碍很常见，很大程度上是由于氧化应激导致 ATP 受损 产生、线粒体自噬，在某些情况下，还包括细胞死亡。减轻或改善这种功能障碍的策略以及 因此，寻求促进发病率和死亡率的降低。外源碳的输送 一氧化碳（CO）因其模拟保护性缺氧的能力而成为一种有前途的策略 途径。 CO 由血红素加氧酶-1 (HO-1) 内源性产生，作为应激反应的一部分。这些 这些分子在脓毒症和组织缺氧模型中具有有效的作用。从机制上讲，线粒体是 这些生物活性气体的主要目标，氧气和二氧化碳都竞相与大量生物活性气体结合 基质内的血红素蛋白。在涉及盲肠的小鼠中使用已建立的细菌性败血症模型 结扎和穿刺，该项目将评估 HO-1/CO 在减轻线粒体功能障碍中的作用 通过调节炎症。我们将研究中性粒细胞，初步数据表明这些 细胞受到 CO 的影响。这些模型将用于表征宿主对脓毒症的反应以及如何 氧滴定影响线粒体功能和存活。我们将评估线粒体功能的变化 和与已知在缺氧期间改变的代谢相关的蛋白质糖基化特征，研究如何 中性粒细胞中的线粒体受氧的影响，评估 HO-1 和 CO 在促进有效和 适当的细菌清除和炎症消退。 在具有丰富专业知识的强有力指导的指导下，这项工作有机会超越观察 围绕围手术期和重症监护环境中的氧气滴定。此外，该项目还包括一个完善的 结构化且严格的职业发展计划，以候选人强大的临床和临床前能力为基础 经验。结合非凡的环境和机构支持，圆满完成 拟议项目的内容将为候选人提供成功所需的技能和经验 作为独立临床科学家，在创新研究中拥有转化专业知识，争夺资金 利基。