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

基本信息

批准号：
9222927
负责人：
Faraaz Ali Shah
金额：
$ 15.72万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-23 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222927
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 use Hour Human Hyperglycemia Hypersensitivity Infection Inflammation Inflammatory Inflammatory Response Insulin Interleukin-1 beta Interleukin-18 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 Activation 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 Infrastructure Research Personnel Research Project Grants Risk Rodent Model Role Route Scientist Sepsis Structure of beta Cell of islet Techniques Testing Therapeutic Time 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 targeted treatment therapy development training opportunity translational study

项目摘要

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.

项目摘要该应用程序是针对受患者的指导研究职业发展奖，标题为“代谢早期营养支持在败血症中的影响：一项翻译研究。“我是肺和重症监护匹兹堡大学医学中心的物理学人需要额外的培训才能发展专业知识作为翻译研究人员，使用败血症动物模型中的代谢评估研究来指导病重疾病患者的干预措施的发展。我的研究项目的核心目标是确定在急性阶段的早期热量支持如何影响新陈代谢和炎症结果败血症。来自鼠标模型的初步数据表明，通过静脉途径提供葡萄糖，即使在败血症的早期，也明显损害葡萄糖耐受性并降低胰岛素敏感性和胰岛素分泌。我们建议这种代谢功能障碍是通过全身性介导的由IL1-β激活引发的细胞因子释放。相反，提供低级葡萄糖败血症早期的肠道途径与循环增加的荷尔蒙增加水平有关， IL1-β和促炎性细胞因子降低，葡萄糖代谢的显着改善。该研究的目的是（1）确定早期热量支持对炎性体激活和败血症的小鼠模型中的代谢，（2）探索肠内激活的潜在保护作用泌尿素骑术在鼠败血症的急性阶段炎症和葡萄糖耐受性方面，（3）翻译有关早期肠葡萄糖在批判性介入试验中的有益作用的发现败血症患者。这些研究将提供有关早期热量支持的最佳时机和途径的见解在化脓性患者的护理中 - 缺乏基本生物学和明确指南的临床实践领域对于医生。该项目将提供独特的翻译培训机会，结合了对通过介入的人类研究，早期热量支持在复杂动物模型中的代谢作用。这项工作将在肺部，过敏和重症监护医学的分区内进行匹兹堡大学（University of Pittsburgh）有着良好的培训身体科学家的记录开发了用于转化研究的基础设施。我得到了坚定的心理支持博士学位的合作伙伴关系，具有鼠模型和代谢方面的专业知识以及医学博士学位，具有关键方面的专业知识疾病和面向患者的研究。我将完成我的MPH培训，以获得正式接触临床研究实践，并已组建一个高级委员会，以提供高级培训炎症，代谢和临床研究领域。