Sepsis and the benefits of permissive hypoxia

项目摘要/摘要 该项目提出了一项为期五年的研究职业发展计划，重点是研究允许的 低氧在脓毒症中的应用拓展了对其潜在机制的认识深度和广度 在这种环境下线粒体功能障碍。目前，氧气给药是应用最广泛的药物。 在住院护理中，并进行自由滴定，以避免潜在的有害时期的低氧血症。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 可能实际上有益于进化的、必要的和保护性的生物过程。在危重疾病中，如 脓毒症，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 世代，有丝分裂，在某些情况下，细胞死亡。减轻或改善这种功能障碍的策略和 因此，寻求促进降低发病率和死亡率。外源交付的碳的交付 一氧化碳(CO)因其能够模拟保护性缺氧而脱颖而出，成为一种有前景的策略 路径。一氧化碳是由血红素加氧酶-1(HO-1)内源性产生的，是应激反应的一部分。这些 在脓毒症和组织缺氧的模型中，分子是非常有用的。从机制上讲，线粒体是 这些生物活性气体的主要目标，氧和一氧化碳都竞争结合到大量 基质中的血球蛋白。利用已建立的小鼠盲肠细菌败血症模型 结扎和穿孔，本项目将评估HO-1/CO在缓解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 细胞受一氧化碳的影响。这些模型将被用来描述宿主对脓毒症的反应以及如何 氧滴定影响线粒体的功能和存活率。我们将评估线粒体功能的变化 和已知与新陈代谢有关的蛋白质糖基化信号在低氧期间改变，研究如何 中性粒细胞线粒体受氧的影响，评估HO-1和CO在促进中性粒细胞中的有效和 适当的细菌清除和炎症消退。 在具有丰富专业知识的强大导师的指导下，这项工作有机会超越观察 在围手术期和重症监护环境中进行氧气滴定。此外，该项目还包括一口井-- 有组织、严谨的职业发展计划，为应聘者提供强大的临床和临床前基础 经验。再加上非凡的环境和制度支持，圆满完成 将为应聘者提供成功所需的技能和经验 作为一名独立的临床科学家竞争资金，在创新研究中拥有翻译专业知识 利基市场。

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.