Sepsis and the benefits of permissive hypoxia

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，重点是研究宽容 缺氧在脓毒症中的应用，以扩大对脓毒症的潜在机制的理解的深度和广度。 线粒体功能紊乱的情况目前，氧气管理是最广泛的管理药物 在医院护理中，并且被自由地滴定以避免低氧血症的潜在有害时期。安装 在几个近缘物种中的证据表明，不仅高氧有害，而且局部组织缺氧 事实上可能对进化的、必需的和保护性的生物过程是有益的。在危重病中，如 在败血症中，线粒体功能障碍是常见的，这在很大程度上是由于氧化应激，导致ATP受损 代，线粒体自噬，在某些情况下，细胞死亡。减轻或改善这种功能障碍的策略， 因此寻求促进发病率和死亡率降低。输送外源输送的碳 一氧化碳（CO）作为一种有前途的策略脱颖而出，因为它能够模拟保护性缺氧 通路作为应激反应的一部分，CO由血红素加氧酶-1（HO-1）内源性产生。这些 分子在脓毒症和组织缺氧的模型中是有效有益的。从机制上讲，线粒体 这些生物活性气体的主要目标，与氧气和CO竞争结合到大量的 血红素蛋白的含量利用已建立的小鼠盲肠细菌性脓毒症模型 本项目将评估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 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 和蛋白质糖基化的签名链接到代谢已知被改变在缺氧期间，研究如何 中性粒细胞中的线粒体受氧的影响，并评估HO-1和CO在促进有效和 适当的细菌清除和炎症消退。 在具有重要专业知识的强大导师的指导下，这项工作有机会超越观察 围手术期和重症监护环境中的氧滴定。此外，该项目还包括一个良好的- 结构化和严格的职业发展计划，以建立在候选人强大的临床和临床前 体验.结合非凡的环境和机构支持， 将为候选人提供必要的技能和经验，成功地 作为一名独立的临床科学家，在创新研究中拥有转化专业知识，竞争资金 利基

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.