Discovery and Characterization of Novel Sepsis Proteome Biomarkers

摘要 该项目将使用基于质谱的蛋白质组学进行生物标志物的发现和验证， 对可能形成基础的强候选生物标志物和生物标志物特征进行早期评估 用于新的临床血液检测这些生物标志物可用作早期检测脓毒症和/或败血症的诊断工具。 促进脓毒症治疗剂的临床开发。 目的：本申请的重点是鉴定和初步生物学、分析和临床 评估脓毒症的生物标志物和生物标志物特征，准备用于确定性分析和临床 验证。 中心假设：使用来自标准化非人灵长类动物的血液样本发现蛋白质组学 脓毒症模型随后在临床样本中进行验证，有可能揭示新的生物标志物和生物标志物 用于脓毒症患者的早期检测、预后和治疗监测的面板。 依据：脓毒症是一种复杂的异质性疾病，通常伴有合并症（例如， 癌症，糖尿病，心血管疾病），可以改变宿主对病原体的反应，从而使其难以 通过发现蛋白质组学确定临床血浆样品中脓毒症特异性生物标志物的谱。我们 建议使用无偏蛋白质组学，结合强大的生物信息学来发现新的预测生物标志物。 我们在实现这些目标方面处于独特的地位，能够获得来自以下国家的表征良好的血浆样品： 使用革兰氏阴性或革兰氏阳性菌血症狒狒模型的历史时间过程实验- 再加上获得NIGMS国家蛋白质组学资源配备了世界一流的仪器， 专业知识此外，定量蛋白质组学和免疫测定法将用于鉴定和验证 脓毒症患者人血浆中的新生物标志物。 具体目标1：在时间进程中早期生物标志物的鉴定和器官定位 狒狒的实验性败血症 具体目标2：临床样本中生物标志物候选物的验证和性能测试。 影响：我们的短期目标是确定狒狒败血症的生物标志物和生物标志物特征， 使用仔细标准化的样本在人体中进行初步生物学、分析和临床评价 和数据集。我们项目的长期目标是提供新的候选生物标志物， 确定性分析和临床验证研究。这些生物标志物将允许早期诊断和监测 脓毒症进展，并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.