Effect of Route of Nutritional Support on Metabolic and Inflammatory Outcomes in Sepsis

 描述（由申请人提供）：项目总结脓毒症是一种危及生命的疾病，其特征是对感染的压倒性炎症反应，脓毒症期间高血糖的发生与器官功能障碍和死亡率增加相关。导致高血糖症发生的因素尚未完全了解，但最近我们的实验室证明，以胃肠外输注葡萄糖的形式进行的营养支持对脓毒症的代谢结果具有重要影响。我们发现败血症和葡萄糖输注都是败血症小鼠模型中代谢功能障碍和高血糖症发展所必需的，并且高血糖症的发展与炎症增加和死亡率增加相关。我们的目的是了解营养支持的途径（肠内或肠外）如何影响脓毒症代谢功能障碍的发展。重症患者以管饲的形式接受肠内营养，尽管全肠外营养的使用已经减少，但肠外葡萄糖输注在维持液和药物载体中仍然很常见。我们假设，与肠外输注相比，脓毒症期间肠内给予葡萄糖将与改善的代谢和炎症结局相关。我们将检验这一假设，目的如下：（1）我们将使用频繁采样的静脉内葡萄糖耐量试验来确定营养支持途径对小鼠内毒素血症中代谢功能障碍和炎症发展的影响，以及（2）我们将确定肠促胰岛素激素胃抑制肽和胰高血糖素样肽1在改善脓毒症期间血糖控制中的作用，以及它们如何影响血糖控制。根据营养支持的途径而有所不同。这些研究将为未来发展旨在改善危重患者结局的转化研究提供平台。这一提议将使候选人，一个医生科学家在培训，有机会进一步发展为一个翻译科学家和动物模型和人类研究之间的桥梁。候选人具有临床研究的最新背景，通过实验室经验和与导师的会议，将获得开发动物模型的经验，以回答仅在人类研究中难以回答的问题。此外，他将进行临床研究硕士学位培训，重点是转化科学，这将加强他在基础科学和临床研究方面的背景。他的导师奥唐纳博士和McVerry博士拥有丰富的资源和知识，使他能够发展成为一名转化科学家，他将得到肺部、过敏和重症监护医学部的大力支持，该部门已证明了对他作为独立临床研究者发展的坚定承诺。

 DESCRIPTION (provided by applicant): Project Summary Sepsis is a life threatening illness characterized by an overwhelming inflammatory response to infection, and the development of hyperglycemia during sepsis is associated with increased organ dysfunction and mortality. The factors contributing to the development of hyperglycemia are not completely understood but recently our laboratory demonstrated that nutritional support, in the form of parenteral infusions of dextrose, can have important effects on metabolic outcomes in sepsis. We found that both septic insult and dextrose infusions were necessary for the development of metabolic dysfunction and hyperglycemia in mouse models of sepsis and that development of hyperglycemia was associated with increased inflammation and increased mortality. Our objective for this proposal is to understand how the route of delivery of nutritional support (enteral or parenteral) influences the development of metabolic dysfunction in sepsis. Critically ill patients receive enteral nutrition in the form of tube feeds, and although the use of total parenteral nutrition has declined, parenteral dextrose infusions remain common in maintenance fluids and as medication carriers. We hypothesize that enteral administration of dextrose during sepsis will be associated with improved metabolic and inflammatory outcomes compared to parenteral infusion. We will test this hypothesis with the following aims: (1) We will determine the effect of route of nutritional support on development of metabolic dysfunction and inflammation in murine endotoxemia with the use of the frequently sampled intravenous glucose tolerance test, and (2) We will determine the roles of the incretin hormones gastric inhibitory peptide and glucagon like peptide 1 in improving glycemic control during sepsis and how they differ based on route of nutritional support. Together these studies will provide the platform for future development of translational investigations targeting improvement in outcomes of critically ill patients. This proposal will allow the candidate, a physician scientist in-training, the opportunity to develop further as a translational scientist and bridge between animal models and human studies. The candidate has a recent background in clinical research and through lab experience and meetings with his mentors will be gaining experience in developing animal models to answer questions that are otherwise difficult to answer solely in human studies. Additionally, he will undertake Master's degree training in Clinical Research with a focus in Translational Science which will strengthen his background in both basic science and clinical research. His mentors, Drs. O'Donnell and McVerry have extensive resources and knowledge to allow him to develop as a translational scientist and he will be well-supported by the Division of Pulmonary, Allergy, and Critical Care Medicine, which has demonstrated strong commitment to his development as an independent clinician investigator.