Metabolic Phenotyping During Stress Hyperglycemia in Cardiac Surgery Patients

项目摘要 研究：应激性高血糖在围手术期很常见，与糖尿病风险增加有关 术后死亡率。反调节荷尔蒙和炎症介质似乎调节急性 然而，导致应激性高血糖和应激性高血糖的病理生理途径 它与糟糕的临床结果的联系还没有被很好地理解。全面代谢图谱(代谢组学) 代表了一种新的工具来检查压力条件下的新陈代谢变化。目前的治疗方法 胰岛素高血糖具有资源利用率高、低血糖风险高等主要局限性。 这项研究提案的主要假设是：1)应激-高血糖与 未知和已知代谢物(即支链氨基酸、酰基肉碱、神经酰胺)和 路径特异性生物标记物(代表炎症、凝血、细胞应激和免疫调节) 心脏手术患者的围手术期，以及2)医源性低血糖风险低，暴露于 长效胰高血糖素样肽-1受体激动剂(GLP-1RA)将改善高血糖和 对手术应激的炎症反应。使用全面的代谢谱方法，这项研究将 对手术应激的代谢和炎症反应的潜在机制提供新的见解 (目标1)。这项研究还将检验接触长效GLP-1RA是否可以改善血糖控制 改善对急性手术应激的炎症反应(目标2)。这些发现将提供证据-- 支持使用新疗法预防和管理住院患者应激性高血糖的原则 布景。候选人和环境：这个K23奖项的候选人是Francisco J Pasquel，医学博士，公共卫生硕士，A 埃默里大学高素质的内分泌学家致力于发展独立资助的职业生涯 翻译研究员。此提案的目标是为应聘者提供额外的高级指导 训练以发展新陈代谢应激反应的机械方面的专门知识，并设计和 执行复杂的临床研究。培训计划的主要组成部分包括：1)来自 在代谢组学、生物标记物和临床试验方面有专长的研究人员；2)学习生物信息学技能， 代谢组学！和网络分析，并通过高级课程授权写作；3)实践经验 代谢组学研究，以及设计/执行嵌套病例对照研究和临床试验；以及4) 参与学术活动，开发独立研究项目，并制定NIH申请。至 成功地实现了他的目标，这位候选人已经组建了一个多学科的、忠诚的导师团队， 所有这些人都成功地指导过初级调查人员，在独立资助方面有很好的记录， 并在与该项目相关的所有研究领域都是国际公认的专家。这项工程将需要 位于埃默里大学，这是一个高度协作的学术环境，为支持 帕斯克尔博士的培训和研究需求。

Project Summary Research: Stress hyperglycemia is common in the perioperative period and is associated with increased risk of postoperative mortality. Counterregulatory hormones and inflammatory mediators appear to modulate the acute biological response to stress; however, the pathophysiological pathways that result in stress hyperglycemia and its link to poor clinical outcomes are not well understood. Comprehensive metabolic profiling (metabolomics) represents a novel tool to examine metabolic changes during stress conditions. The current approach to treat hyperglycemia with insulin has major limitations including high resource utilization and high risk of hypoglycemia. The overarching hypotheses of this research proposal are that: 1) Stress-hyperglycemia is associated with changes in unknown and known metabolites (i.e. branched-chain amino acids, acylcarnitines, ceramides) and path-specific biomarkers (representing inflammation,!coagulation, cell stress, and immune modulation) in the perioperative period in cardiac surgery patients, and 2) with a low risk of iatrogenic hypoglycemia, exposure to a long acting glucagon like peptide-1 receptor agonist (GLP-1 RA) will ameliorate the hyperglycemic and inflammatory response to surgical stress. Using comprehensive metabolic profiling methods, this study will provide new insights into the mechanisms underlying the metabolic and inflammatory responses to surgical stress (Aim 1). This study will also examine whether exposure to a long acting GLP-1 RA can improve glycemic control and ameliorate the inflammatory response to acute surgical stress (Aim 2). These findings will provide proof-of principle to support the use of novel therapies to prevent and manage stress hyperglycemia in the inpatient setting. Candidate and Environment: The candidate for this K23 award is Francisco J Pasquel, MD, MPH, a highly qualified endocrinologist at Emory University committed to developing a career as an independently funded translational researcher. The goal of this proposal is to provide the candidate with additional advanced mentored training to develop expertise in mechanistic aspects of the metabolic response to stress and the design and execution of complex clinical studies. Key components of the training plan include: 1) mentorship from investigators with expertise in metabolomics, biomarkers, and clinical trials; 2) learning skills in bioinformatics, metabolomics!and network analysis, and grant writing through advanced coursework; 3) hands-on experience metabolomics research, and design/execution of a nested case-control study and a clinical trial; and 4) participation in scholarly activities to develop independent research projects, and formulate NIH applications. To successfully achieve his goals, the candidate has assembled a multidisciplinary and committed group of Mentors, all of whom have successfully mentored junior investigators, have a strong track record of independent funding, and are internationally recognized experts in all areas of research related to this project. The project will take place at Emory University, a highly collaborative academic environment that provides an ideal setting to support Dr. Pasquel's training and research needs.