Metabolic Effects of Early Nutritional Support in Sepsis: A Translational Investigation

项目摘要 本申请表是关于以病人为导向的研究事业发展奖的申请表，标题为 脓毒症患者早期营养支持的效果：一项翻译研究。我是肺部重症监护室 匹兹堡大学医学中心的内科医生，他需要额外的培训来发展专业知识 作为一名翻译研究人员，在脓毒症动物模型中使用代谢评估研究来指导 发展对危重病人的干预措施。我的研究项目的中心目标是 确定早期热量支持如何影响急性期的新陈代谢和炎症结果 败血症。来自我们的小鼠模型的初步数据表明，通过静脉途径提供葡萄糖， 即使在脓毒症早期处于较低水平，也会显著损害糖耐量并降低胰岛素。 敏感度和胰岛素分泌。我们认为这种代谢障碍是通过全身性的 炎症体激活IL-1-β引发的细胞因子释放。相比之下，通过以下方式提供低水平葡萄糖 脓毒症早期的肠道途径与循环中的胰岛素激素水平升高有关， 降低IL-1-β和促炎细胞因子，显著改善糖代谢。这个 本研究的目的是(1)确定早期热量支持对炎性小体激活和 脓毒症小鼠模型的代谢，(2)探讨肠内激活对脓毒症的潜在保护作用 胰岛素激素途径在小鼠脓毒症急性期炎症和糖耐量中的作用 在危重病先导性介入试验中翻译早期肠内葡萄糖有益作用的研究结果 脓毒症患者。这些研究将为早期热量支持的最佳时机和途径提供洞察力 在脓毒症患者的护理--一个缺乏基础生物学和明确指南的临床实践领域 对内科医生来说。该项目将提供一个独特的翻译培训机会，将探索 早期热量支持在复杂动物模型中的代谢效应与先导性干预性人类研究。 这项工作将在肺、过敏和重症监护医学部内进行 匹兹堡大学，这所大学在培养内科科学家方面有着出色的记录，而且 为开展翻译研究开发了基础设施。我得到了一位忠诚的导师的支持 博士和医学博士的合作伙伴关系，前者擅长小鼠模型和新陈代谢，后者擅长危重疾病 疾病和以病人为中心的研究。我将完成公共卫生硕士培训，以获得正式的临床经验。 并成立了一个咨询委员会，在 炎症、新陈代谢和临床研究领域。

PROJECT ABSTRACT This application is for a Mentored Patient-Oriented Research Career Development Award entitled “Metabolic Effects of Early Nutritional Support in Sepsis: A Translational Investigation.” I am a pulmonary and critical care physician at the University of Pittsburgh Medical Center who requires additional training to develop expertise as a translational researcher using metabolic assessment studies in animal models of sepsis to guide the development of interventions in patients with critical illness. The central objective of my research project is to determine how early caloric support impacts metabolism and inflammatory outcomes in the acute phase of sepsis. Preliminary data from our mouse models suggest that provision of dextrose via an intravenous route, even at low levels early in the course of sepsis, markedly impairs glucose tolerance and decreases insulin sensitivity and insulin secretion. We propose that this metabolic dysfunction is mediated through systemic cytokine release initiated by inflammasome activation of IL1-β. In contrast, provision of low-level dextrose by the enteral route during early sepsis, is associated with increased levels of circulating incretin hormones, decreased IL1-β and pro-inflammatory cytokines, and significant improvements in glucose metabolism. The aims of the study are (1) to determine the effects of early caloric support on inflammasome activation and metabolism in a mouse model of sepsis, (2) to explore the potentially protective role of enteral activation of the incretin hormone pathway on inflammation and glucose tolerance in the acute phase of murine sepsis, and (3) to translate findings on the beneficial role of early enteral dextrose in a pilot interventional trial in critically-ill patients with sepsis. These studies will provide insight into the optimal timing and route of early caloric support in the care of septic patients—an area of clinical practice lacking in fundamental biology and clear guidelines for physicians. The project will provide a unique translational training opportunity that combines exploration of the metabolic effects of early caloric support in complex animal models with a pilot interventional human study. The work will be conducted within the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Pittsburgh, which has an outstanding record of training physician-scientists and a highly developed infrastructure for the conduct of translational studies. I am supported by a committed mentoring partnership of a PhD, with expertise in murine models and metabolism, and an MD, with expertise in critical illness and patient-orientated research. I will complete my MPH training to gain formal exposure to clinical research practices and have assembled an Advisory Committee to provide advanced training exposure in the areas of inflammation, metabolism, and clinical research.