Metabolic Phenotyping During Stress Hyperglycemia in Cardiac Surgery Patients

项目摘要 研究：应激性高血糖症在围手术期很常见，并且与以下风险增加有关： 术后死亡率反调节激素和炎症介质似乎调节急性炎症反应。 对应激的生物学反应;然而，导致应激性高血糖症的病理生理学途径， 它与不良临床结果之间的联系还没有得到很好的理解。代谢组学（Metabolomics） 代表了一种新的工具，以检查代谢变化期间的压力条件。目前的治疗方法 使用胰岛素的高血糖症具有主要的局限性，包括高资源利用和低血糖症的高风险。 本研究的主要假设是：1）应激性高血糖与 未知和已知代谢物（即支链氨基酸、酰基肉毒碱、神经酰胺）的变化，以及 路径特异性生物标志物（代表炎症，！凝血、细胞应激和免疫调节）， 心脏手术患者围手术期，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-1 RA）将改善高血糖和 手术应激的炎症反应。使用综合代谢分析方法，本研究将 为外科应激的代谢和炎症反应机制提供了新的见解 (Aim 1）。本研究还将检查暴露于长效GLP-1 RA是否可以改善血糖控制 并改善对急性手术应激的炎症反应（目的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 设置.候选人和环境：这个K23奖的候选人是弗朗西斯科J帕斯奎尔，医学博士，公共卫生硕士， 埃默里大学的一位高素质的内分泌学家致力于发展自己的职业生涯， 翻译研究员本提案的目标是为候选人提供额外的高级指导 培训，以发展对压力的代谢反应的机制方面的专业知识， 进行复杂的临床研究。培训计划的主要组成部分包括：1）来自 具有代谢组学，生物标志物和临床试验专业知识的研究人员; 2）学习生物信息学技能， 代谢组学！和网络分析，并通过高级课程授予写作; 3）实践经验 代谢组学研究，以及巢式病例对照研究和临床试验的设计/执行;以及4） 参与学术活动，开发独立的研究项目，并制定NIH应用程序。到 成功地实现了他的目标，候选人已经聚集了一个多学科和承诺的导师组， 他们都成功地指导了初级调查员，有着良好的独立资助记录， 并且是与该项目相关的所有研究领域的国际公认专家。该项目将需要 埃默里大学，一个高度协作的学术环境，提供了一个理想的环境，以支持 博士帕斯奎尔的训练和研究需求。

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.