Discovery and Characterization of Novel Sepsis Proteome Biomarkers

新型脓毒症蛋白质组生物标志物的发现和表征

• 批准号: 10364288
• 负责人: FLOREA LUPU
• 金额: $ 55.43万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364288
• 关键词: Accounting; Acute; Address; Bacteremia; Bacteria; Bioinformatics; Biological; Biological Markers; Blood Tests; Blood specimen; Cardiovascular Diseases; Cause of Death; Cessation of life; Clinical; Complex; Coupled; Data; Data Set; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Dose; Early Diagnosis; Early treatment; Escherichia coli; Evaluation; Foundations; Functional disorder; Future; Goals; Hospital Costs; Human; Immune response; Immune system; Immunoassay; Infection; Infrastructure; Life; Malignant Neoplasms; Mass Spectrum Analysis; Methods; Mission; Modeling; Monitor; National Institute of General Medical Sciences; Oklahoma; Organ; Papio; Pathologist; Patients; Plasma; Positioning Attribute; Prognosis; Proteome; Proteomics; Public Health; Race; Research; Resources; Sampling; Scientist; Sepsis; Septic Shock; Septicemia; Source; Specialist; Standardization; Staphylococcus aureus; Syndrome; Testing; Therapeutic; Time; Tissue Sample; Translating; Validation; base; biomarker development; biomarker discovery; biomarker panel; biomarker signature; biomarker validation; candidate marker; clinical development; cohort; comorbidity; differential expression; drug development; early detection biomarkers; experience; experimental study; improved outcome; instrumentation; medical attention; microbial; multidisciplinary; nonhuman primate; novel; novel marker; novel therapeutics; pathogen; patient stratification; performance tests; personalized medicine; predictive marker; protein biomarkers; proteomic signature; research clinical testing; septic patients; specific biomarkers; statistics; targeted treatment; tool; treatment strategy; validation studies

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.

抽象的 该项目将使用基于质谱的蛋白质组学来发现和验证生物标志物，并将 对可能构成基础的强大候选生物标志物和生物标志物特征进行早期评估 用于新的临床血液测试。这些生物标志物可用作早期检测败血症和/或 促进脓毒症治疗方法的临床开发。 目标：本应用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，为最终的分析和临床做好准备 验证。 中心假设：使用来自标准化良好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 用于脓毒症患者早期检测、预后和治疗监测的面板。 理由：脓毒症是一种复杂的异质性疾病，经常伴有合并症（例如， 癌症、糖尿病、心血管疾病），它们可以改变宿主对病原体的反应，从而使其变得困难 通过临床血浆样本中的发现蛋白质组学来确定脓毒症特异性生物标志物谱。我们 建议使用公正的蛋白质组学，结合强大的生物信息学来发现新的预测生物标志物。 我们处于实现这些目标的独特位置，可以从以下来源获得经过充分表征的血浆样本 使用革兰氏阴性或革兰氏阳性菌血症的狒狒模型进行历史时间过程实验 - 加上配备世界一流仪器的 NIGMS 国家蛋白质组学资源 专业知识。此外，定量蛋白质组学和免疫测定将用于鉴定和验证 脓毒症患者血浆中的新型生物标志物。 具体目标 1： 早期生物标志物的鉴定和器官图谱 狒狒实验性败血症。 具体目标 2：临床样本中候选生物标志物的验证和性能测试。 影响：我们的短期目标是确定狒狒和狒狒败血症的生物标志物和生物标志物特征 使用精心标准化的样本对人体进行初步生物学、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志物，为 明确的分析和临床验证研究。这些生物标志物将有助于早期诊断和监测 脓毒症进展并将有助于患者分层进行靶向治疗。