Discovery and Characterization of Novel Sepsis Proteome Biomarkers

摘要 该项目将使用基于质谱学的蛋白质组学来发现和验证生物标记物，并将 对可能构成基础的强有力的候选生物标志物和生物标志物签名进行早期评估 做新的临床验血。这些生物标志物可用作脓毒症和/或脓毒症的早期诊断工具 促进脓毒症治疗的临床发展。 目的：该应用的重点是鉴定和初步的生物学、分析和临床。 脓毒症的生物标志物和生物标志物签名的评估将为最终的分析和临床做好准备 验证。 中心假设：利用标准化的非人类灵长类动物的血液样本发现蛋白质组学 脓毒症模型在临床样本中验证后有可能揭示新的生物标志物和生物标志物 脓毒症患者早期发现、预后和治疗监测的小组。 理论基础：脓毒症是一种复杂的、异质性的疾病，经常合并有并发症(例如， 癌症、糖尿病、心血管疾病)，这些疾病会改变宿主对病原体的反应，从而使 目的：通过发现临床血浆标本中的蛋白质组学，确定脓毒症特异性生物标志物的谱。我们 建议使用无偏见的蛋白质组学，结合强大的生物信息学来发现新的预测生物标记物。 我们在实现这些目标方面处于独特的地位，可以从 使用革兰氏阴性或革兰氏阳性菌血症的狒狒模型进行的历史时间进程实验-- 同时获得NIGMS国家蛋白质组资源，配备世界一流的仪器和 专业知识。此外，定量蛋白质组学和免疫分析将用于鉴定和验证 脓毒症患者血浆中的新生物标志物。 具体目标1：早期生物标志物的识别和器官定位 在狒狒身上发生实验性败血症。 具体目标2：对临床样本中的候选生物标记物进行验证和性能测试。 影响：我们的短期目标是确定狒狒败血症的生物标记物和生物标记物签名 使用仔细标准化的样本在人体上进行初步的生物学、分析和临床评估 和数据集。我们项目的长期目标是提供新的候选生物标记物 权威的分析和临床验证研究。这些生物标志物将使早期诊断和监测 脓毒症的进展，将有助于患者分层的靶向治疗。

ABSTRACT This project will use mass spectrometry-based proteomics for biomarker discovery and validation and will perform early evaluation of strong candidate biomarkers and biomarker signatures that might form the foundation for new clinical blood tests. These biomarkers can be used as diagnostic tools for early detection of sepsis and/or facilitate the clinical development of sepsis therapeutics. Objectives: The focus of this application is on the identification and initial biological, analytical and clinical evaluation of biomarkers and biomarker signatures for sepsis that will be ready for definitive analytical and clinical validation. Central hypothesis: Discovery proteomics using blood samples from well-standardized non-human primate sepsis models followed by validation in clinical samples has the potential to reveal new biomarker and biomarker panels for early detection, prognosis and therapy monitoring of sepsis patients. Rationale: Sepsis is a complex, heterogeneous disease that frequently is complicated with comorbidities (e.g., cancer, diabetes, cardiovascular disease) that can alter the host responses to pathogens, thus making it difficult to determine the spectrum of sepsis-specific biomarkers by discovery proteomics in clinical plasma samples. We propose to use unbiased proteomics, coupled with robust bioinformatics to discover novel predictive biomarkers. We are in a unique position to achieve these goals, having access to well-characterized plasma samples from historical time-course experiments using baboon models of Gram-negative or Gram-positive bacteremia – coupled with access to a NIGMS national proteomics resource equipped with world-class instrumentation and expertise. Further, quantitative proteomics and immunoassays will be used for qualification and validation of the novel biomarkers in human plasma from sepsis patients. Specific Aim 1: Identification and organ mapping of early stage biomarkers during the time course of experimental sepsis in baboons. Specific Aim 2: Validation and performance testing of biomarker candidates in clinical samples. Impact: Our short-term goals are to identify biomarkers and biomarker signatures for sepsis in baboons and perform the initial biological, analytical and clinical evaluation in humans using carefully standardized samples and datasets. The long-term goal of our project is to deliver novel candidate biomarkers that are ready for definitive analytical and clinical validation studies. These biomarkers will allow early diagnosis and monitoring of sepsis progression and will help patient stratification for targeted therapies.