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.
Oxygen delivery remains a cornerstone of healthcare delivery in the in the critically ill, however only little attention has been afforded to the concepts of permissive hypoxia and carbon monoxide mediated pseudo- hypoxia, despite emerging evidence of their protective anti-inflammatory effects. In disease states such as sepsis where there is increased oxidative stress and reactive oxygen species production, mitochondrial dysfunction is especially common resulting in both dysregulated function and decreased energy production. As a first step towards understanding this relationship and guiding the titration of oxygen in the acutely ill, this project explores the role of permissive hypoxia in the amelioration of mitochondrial dysfunction in a murine model of intraabdominal sepsis.
