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

脓毒症早期营养支持的代谢效应：一项转化研究

• 批准号: 9769833
• 负责人: Faraaz Ali Shah
• 金额: $ 15.74万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769833
• 关键词: Acute; Advisory Committees; Affect; Animal Model; Area; Attenuated; Biochemical; Biology; Caring; Chronic; Clinical Research; Clinical Trials; Complex; Critical Care; Critical Illness; Data; Development; Doctor of Philosophy; Endotoxins; Enteral; Exposure to; Functional disorder; Glucose; Glucose Intolerance; Guidelines; Hormone secretion; Hormone use; Hour; Human; Hyperglycemia; Hypersensitivity; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Insulin; Interleukin-1 beta; Interleukin-18; Intervention; Intervention Studies; Intervention Trial; Intravenous; Investigation; Learning; Life; Link; Lung; Mediating; Medical center; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolic; Metabolic dysfunction; Metabolism; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutritional Support; Organ; Outcome; Pathway interactions; Patients; Pattern; Peripheral; Phase; Physicians; Pilot Projects; Play; Process; Production; Research; Research Design; Research Project Grants; Risk; Rodent Model; Role; Route; Scientist; Sepsis; Structure of beta Cell of islet; Techniques; Testing; Therapeutic; Tissues; Training; Translating; Universities; Up-Regulation; Work; adverse outcome; bench to bedside; clinical practice; cytokine; glucagon-like peptide 1; glucose metabolism; glucose tolerance; human study; impaired glucose tolerance; improved; incretin hormone; insight; insulin secretion; insulin sensitivity; insulin signaling; metabolic abnormality assessment; mortality; mouse model; nutrition; pathogen; prevent; protein complex; response; septic; septic patients; targeted treatment; therapy development; training opportunity; translational scientist; translational study

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.

项目摘要 此应用程序是一个指导病人为导向的研究职业发展奖题为“代谢 早期营养支持在脓毒症中的作用：一项转化研究。我是一个肺和重症监护 匹兹堡大学医学中心的医生，需要额外的培训来发展专业知识 作为一名翻译研究人员，在败血症动物模型中使用代谢评估研究来指导 发展对危重病患者的干预。我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代谢和炎症结局， 败血症来自我们小鼠模型的初步数据表明，通过静脉途径提供葡萄糖， 即使在脓毒症早期的低水平，也明显损害葡萄糖耐量并降低胰岛素 敏感性和胰岛素分泌。我们认为，这种代谢功能障碍是通过全身性介导的， 由IL 1-β的炎性体活化引发的细胞因子释放。相比之下，低水平葡萄糖的供应， 早期脓毒症期间的肠内途径，与循环肠促胰岛素激素水平的增加有关， IL 1-β和促炎细胞因子减少，葡萄糖代谢显著改善。的 本研究的目的是（1）确定早期热量支持对炎性小体激活的影响， （2）探讨肠内激活对脓毒症小鼠模型代谢的潜在保护作用， 肠促胰岛素激素途径对小鼠脓毒症急性期炎症和葡萄糖耐量的影响，以及（3） 在危重病患者的初步干预性试验中， 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见解 在脓毒症患者的护理中，这是一个缺乏基础生物学和明确指导方针的临床实践领域 对于医生来说。该项目将提供一个独特的翻译培训机会，结合探索 早期热量支持对复杂动物模型的代谢影响，并进行了初步干预性人体研究。 这项工作将在肺，过敏和重症监护医学部进行， 匹兹堡大学在培养医学科学家方面有着出色的记录， 为开展翻译研究建立了基础设施。我得到了一个坚定的指导， 合作伙伴的博士，在小鼠模型和代谢的专业知识，和一个医学博士，在关键的专业知识， 疾病和以病人为导向的研究。我将完成我的MPH培训，以获得正式接触临床 研究实践，并组建了一个咨询委员会，以提供先进的培训接触， 炎症、代谢和临床研究领域。