Translational Metabolomics in Critical Care

脓毒症和其他严重疾病仍然是人类健康的重大危害。脓毒症尤其具有挑战性 因为它与巨大的异质性有关，这种异质性使诊断性和预测性的识别保持在同一水平上， 标志物和有效的药物治疗难以捉摸。药物不良反应是前六位的主要原因之一 的发病率和死亡率。为了解决这些问题，我的研究项目采用了翻译 代谢组学是分析和实验技术之间的桥梁， 代谢组学的临床应用。具体而言，它旨在将代谢组学应用于：1）在- 提高对代谢过程的理解，这些代谢过程是败血症等临床挑战性问题的基础; 2)改善药物反应预测（药物代谢组学），包括药物不良反应。我们有 一种创新的猪败血症模型，忠实地再现了人类的情况，新的即时护理（POC） 技术，并可以使用一系列分析平台（包括液相色谱）分析生物样本 （LC）-质谱（MS）和定量核磁共振（NMR）。我们最近的进展 导致了关于脓毒症对L-肉毒碱的反应机制的重要发现， 适应性和药物不良反应。我们的药物代谢组学方法引入了Meta- bolic激发，以确定潜在的脓毒症表型。我们还确定了血液中的肉毒碱浓度- 作为代谢应激的信号，其可能易导致不良药物反应。根据MIRA (R35)应用程序，我的计划的首要和长期目标是将代谢组学从知识 从发现到实施，这将推动重症患者护理的转变。到 为了实现这一目标，我们将解决三个关键的知识差距：1）代谢危机的时间轴的重大疾病 像败血症，它的轨迹，知之甚少; 2）对机制的理解有限， 有助于脓毒症中代谢适应性和灵活性的基础;以及3）缺乏 对药物反应差异的基础代谢机制的基本理解，包括 药物不良反应。在与分析化学家的富有成效的持续合作的帮助下， 和生物信息学家，我们希望这项工作将带来一个范式转变的理解机制， 脓毒症和药物反应的物理基础。从长远来看，我们预计，发现脓毒症诱导的Meta， 改变肉毒碱和酰基肉毒碱配置文件证明，bolic缺陷，将导致识别新的 药物靶向机会、诊断和预后生物标志物候选物以及新的POC技术， 推动败血症的早期可靠检测。此外，我们还将对这些机制有新的认识， 正确和区分药物反应，包括ADR。总的来说，这项工作将提供一种精确的医学 有效治疗脓毒症的指令，推动信息充分的适应性临床试验的发展， 标志，改善人类健康。

Sepsis and other critical illnesses remain significant hazards to human health. Sepsis is particularly challenging because it is associated with great heterogeneity that has kept the identification of diagnostic and predictive bi- omarkers and effective pharmacotherapy elusive. Adverse drug reactions are among the top six leading cause of morbidity and mortality in the nation. To tackle these problems, my research program employs Translational Metabolomics which bridges the translational gap between analytical and experimental techniques and the clinical application of the science of metabolomics. Specifically, it is aimed at applying metabolomics to: 1) in- crease understanding of the metabolic processes that underlie clinically challenging problems like sepsis; and 2) improve prediction of drug response (pharmacometabolomics), including adverse drug reactions. We have an innovative swine model of sepsis that faithfully recapitulates the human situation, novel point-of-care (POC) technology and can assay biospecimens using a range of analytical platforms including liquid chromatography (LC)-mass spectroscopy (MS) and quantitative nuclear magnetic resonance (NMR). Our recent progress has led to paramount findings about the mechanisms that underlie sepsis responsiveness to L-carnitine, metabolic adaptiveness and adverse drug reactions. Our pharmacometabolomics approach introduced the idea of meta- bolic provocation to identify latent sepsis phenotypes. We have also determined that blood carnitine concentra- tions serve as a signal of metabolic stress that may predispose to adverse drug reactions. Under this MIRA (R35) application, the overarching and long-term goal of my program is to move metabolomics from knowledge discovery to implementation that will drive the transformation of the care of patients with critical illnesses. To achieve this, we will address three key gaps in knowledge: 1) The metabolic crisis timeline of critical illnesses like sepsis is, and its trajectories are, poorly understood; 2) there is limited understanding of the mechanistic underpinnings that contribute to metabolic adaptiveness and flexibility in sepsis; and 3) there is an absence of fundamental understanding of the metabolic mechanisms that underlie the variance in drug response including adverse drug reactions. With the assistance of productive, ongoing collaborations with an analytical chemist and bio-informaticist, we expect this work will bring about a paradigm shift in the understanding of the mecha- nistic underpinnings of sepsis and drug response. Long-term, we expect that the found sepsis-induced meta- bolic defects, evidenced by altered carnitine and acyl-carnitine profiles, will lead to the identification of new drug target opportunities, diagnostic and prognostic biomarker candidates and new POC technology that will drive the early, reliable detection of sepsis. In addition, we will have new insights into the mechanisms that di- rect and differentiate drug response including ADRs. Collectively, this work will provide a precision medicine directive for the effective treatment of sepsis, fuel the advancement of well-informed adaptive clinical trial de- sign, and improve human health.