Mass Spectrometry-Based Biomarker Discovery

基于质谱的生物标志物发现

基本信息

批准号：
7688832
负责人：
Subramaniam Pennathur
金额：
$ 38.63万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-07 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7688832
关键词：
3-chlorotyrosine 3-nitrotyrosine Acetylcysteine Acute Acute respiratory failure Address Affect Alveolar Amino Acids Ancillary Study Antioxidants Apoptosis Applications Grants Area Arts Azathioprine Biological Markers Blood capillaries Carbon Monoxide Cells Cessation of life Chronic Chronic Obstructive Airway Disease Clinical Clinical Research Clinical Trials Clinical Trials Network Cross-Sectional Studies Data Development Diagnosis Diagnostic Diffuse Disease Disease Progression Effectiveness Enrollment Epithelial Cells Fibrosis Figs - dietary Frequencies Gases Glutathione Goals Hamman-Rich syndrome Heterogeneity Human Incidence Individual Inflammatory Laboratories Lung diseases Mass Fragmentography Mass Spectrum Analysis Measures Mediating Molecular Profiling Morbidity - disease rate Multi-Institutional Clinical Trial Myofibroblast Natural regeneration Oral Outcome Oxidation-Reduction Oxidative Stress Oxidative Stress Pathway Parents Pathogenesis Pathway interactions Patients Performance Pharmaceutical Preparations Pharmacotherapy Phase III Clinical Trials Physiological Placebos Plasma Plasma Proteins Post-Translational Protein Processing Prednisone Prevalence Progressive Disease Protein Profiling Microarrays Proteins Proteome Proteomics Randomized Reactive Nitrogen Species Reactive Oxygen Species Request for Applications Research Respiratory Failure Respiratory physiology Risk Role Sampling Severities Severity of illness Signal Transduction Stratification Subgroup Techniques Testing Therapeutic Intervention Therapeutic immunosuppression Tissues Tyrosine United States United States National Institutes of Health Vital capacity Volunteer Group Walking abstracting antioxidant therapy base capillary cell injury cell type clinical application clinical phenotype cohort conventional therapy dityrosine drug discovery effective therapy functional loss high risk injury and repair insight lung injury mortality novel novel strategies oxidation protein profiling public health relevance repaired response success treatment strategy volunteer

项目摘要

DESCRIPTION (provided by applicant): Humans with Idiopathic pulmonary fibrosis (IPF) are at a high risk for progressive respiratory failure, acute exacerbations of the disease and death. There is a recognized need for novel mechanism-based biomarkers that accurately predict pathways activated in the individuals with progressive IPF and those that are likely to be more responsive to specific therapies. This proposal is in response to a request of application (RFA-HL-08- 001) and directly addresses this critical gap in our diagnostic capability. The overall goals of this proposal are to develop and validate novel biomarkers using a mass spectrometry (MS)-based approach followed by a microarray-based proteomic platform combined with MS to elucidate pathways that contribute to IPF progression. A major focus of the proposal will involve development of a microarray-based proteomic platform that can readily be transferred to high throughput clinical applications. Using highly sensitive and specific gas chromatography MS we have recently characterized and validated specific markers of oxidative stress in human plasma. These markers serve as molecular fingerprints for specific oxidation pathways. We have also developed a novel microarray based proteomic platform that can accurately identify and screen modified proteins from the plasma proteome. We predict that using our novel approach we will be able to identify differential oxidation of plasma proteins which uniquely identifies subsets of IPF patients at risk for progressive disease and those likely to benefit from redox-modulating drug therapies. PUBLIC HEALTH RELEVANCE: IPF is a progressive and ultimately fatal disease for which no effective drug therapies currently exist. Finding effective therapies for this disease has been limited by the lack of reliable biomarkers of disease activity/progression. Heterogeneity in responsiveness to specific treatments may also limit the ability to demonstrate effectiveness of a particular treatment strategy. This study will define novel plasma biomarkers in IPF patients with progressive disease and identify specific patient subgroups that respond favorably to redox- modulating drug therapy. (End of Abstract)

描述（由申请人提供）：患有特发性肺纤维化（IPF）的人发生进行性呼吸衰竭、疾病急性恶化和死亡的风险很高。人们认识到需要基于新型机制的生物标志物来准确预测进行性 IPF 患者和可能对特定疗法更敏感的患者中激活的途径。该提案是为了响应申请请求 (RFA-HL-08-001)，并直接解决我们诊断能力中的这一关键差距。该提案的总体目标是使用基于质谱 (MS) 的方法开发和验证新型生物标志物，然后将基于微阵列的蛋白质组学平台与 MS 相结合，以阐明促进 IPF 进展的途径。该提案的一个主要重点将涉及开发基于微阵列的蛋白质组平台，该平台可以轻松转移到高通量临床应用。最近，我们利用高灵敏度和特异性的气相色谱 MS 表征并验证了人血浆中氧化应激的特异性标记物。这些标记物充当特定氧化途径的分子指纹。我们还开发了一种基于微阵列的新型蛋白质组平台，可以准确识别和筛选血浆蛋白质组中的修饰蛋白质。我们预测，利用我们的新方法，我们将能够识别血浆蛋白的差异氧化，从而独特地识别有进展性疾病风险的 IPF 患者亚群以及可能受益于氧化还原调节药物治疗的患者亚群。公共卫生相关性：IPF 是一种进行性且最终致命的疾病，目前尚无有效的药物疗法。由于缺乏疾病活动/进展的可靠生物标志物，寻找这种疾病的有效疗法受到限制。对特定治疗的反应异质性也可能限制证明特定治疗策略有效性的能力。这项研究将定义患有进展性疾病的 IPF 患者的新型血浆生物标志物，并确定对氧化还原调节药物治疗有良好反应的特定患者亚组。（摘要完）