Translational Metabolomics in Critical Care

败血症和其他危重疾病仍然是对人类健康的重大危害。败血症尤其具有挑战性。 因为它与巨大的异质性有关，这使得对诊断和预测的识别成为可能。 征兆和有效的药物治疗难以捉摸。药品不良反应位居前六位 全国的发病率和死亡率。为了解决这些问题，我的研究项目使用了Translative 代谢组学，它弥合了分析和实验技术之间的翻译差距，以及 代谢组学的临床应用。具体地说，它旨在将代谢组学应用于：1)在- 加深对导致败血症等临床挑战性问题的代谢过程的理解；以及 2)改进药物反应(药物代谢组学)的预测，包括药物不良反应。我们有 一种创新的猪败血症模型，真实地概括了人类的情况，新颖的护理点(POC) 技术，并可以使用包括液相色谱在内的一系列分析平台来检测生物旋毛虫 (LC)-质谱学(MS)和定量核磁共振(核磁共振)。我们最近的进展是 导致了关于脓毒症对L的反应机制的最重要的发现-肉碱，代谢 适应性和药物不良反应。我们的药物代谢组学方法引入了代谢组学的概念。 波尔丁刺激以确定潜在的脓毒症表型。我们还确定了血肉碱浓缩物- 毒素是新陈代谢应激的信号，可能导致药物不良反应。在这辆米拉车下 (R35)应用，我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，这将推动危重疾病患者护理的转变。至 实现这一点，我们将解决知识中的三个关键差距：1)危重疾病的代谢危机时间表 就像脓毒症一样，它的轨迹也鲜为人知；2)对其发病机制的了解有限 有助于败血症的代谢适应性和灵活性的基础；以及3)缺乏 对药物反应差异背后的代谢机制的基本理解包括 药物不良反应。在与分析化学家富有成效的持续合作的帮助下 和生物信息学家，我们预计这项工作将带来对机械的理解的范式转变- 败血症和药物反应的Nistic基础。从长远来看，我们预计已发现的败血症诱导的新陈代谢- 由肉碱和酰基肉碱轮廓改变所证明的曲线型缺陷将导致新的 药物靶向机会、诊断和预后生物标记物候选对象以及将 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见解-- 纠正和区分药物反应，包括不良反应。总体而言，这项工作将提供一种精准的医疗 为有效治疗脓毒症提供指导，推动知情适应性临床试验的进展。 签署，并改善人类健康。

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.