Complete Human Peptide- and MRM-Atlas

完整的人类肽和 MRM 图谱

• 批准号: 7855123
• 负责人: LEROY E HOOD
• 金额: $ 227.48万
• 依托单位: INSTITUTE FOR SYSTEMS BIOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7855123
• 关键词: Algorithms; Antibodies; Arts; Atlases; Biological Assay; Cleaved cell; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; Code; Collection; Communities; Computer Simulation; Computer software; Data; Databases; Development; Diagnostic; Disease; Early Diagnosis; Epitopes; Evaluation; Gene Expression Profile; Genes; Genome; Genomics; Goals; Health; Health Status; Human; Hydrophobicity; In Vitro; Information Technology; Label; Link; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Measures; Medicine; Mining; Molecular; Molecular Profiling; Nature; Operant Conditioning; Outcome; Patient Care; Patient Rights; Patients; Peptide Fragments; Peptides; Personal Satisfaction; Pharmaceutical Preparations; Plasma; Post-Translational Protein Processing; Production; Protein Isoforms; Proteins; Proteome; Proteomics; Reagent; Relative (related person); Research; Resources; Sampling; Science; Set protein; Stratification; System; Techniques; Technology; Therapeutic; Time; Training; base; cancer Biomedical Informatics Grid; cancer genome; clinical practice; clinically relevant; cohort; database design; design; direct application; human Numb protein; human data; human disease; human tissue; improved; indexing; innovative technologies; insight; instrument; instrumentation; interest; metabolomics; multiple reaction monitoring; new technology; outcome forecast; phenome; prognostic; programs; protein metabolite; public health relevance; stable isotope; synthetic peptide; tool

DESCRIPTION (provided by applicant): Personalized medicine will depend on molecular signatures to match the right patients to the right drugs, first in clinical trials, then in clinical practice. Personalized medicine is a new paradigm in which information technology, science, and clinical treatment are synergistically integrated to improve health and patient well-being. This approach requires unusually large databases, relating both molecular and clinical data, such that patients can be proactively selected for the most appropriate therapies. Towards achieving personalized medicine, it is crucial to begin developing sensitive and reliable assays to quantitatively detect the tri-omic signatures of gene expression, metabolite and protein changes and distribution. For proteins, we must measure the homeostatic or aberrant distribution in order to help define the current health status or disease state. The specific, simple and immediate goal of our proposal is to develop a complete proteome centric database to allow the targeted analysis of any human protein(s) of interest through the use of multiple-reaction- monitoring (MRM). We will develop and provide a proteotypic peptide fragmentation database, of at least 4 peptides per human protein-coding gene, with verified rapid and accurate MRM based mass spectrometric assays to unambiguously identify and quantify any protein of the human proteome in a multitude of samples. The estimated number of human protein-coding genes is 20,332 based on strict criteria, but can be as high as 25,000. Our approach involves building a comprehensive, publicly available database for users to query and download all the information required to rapidly implement targeted assays against proteins of interest in plasma or other human tissues. In addition, this effort provides a verified proteotypic peptide database for designing peptide-epitope capture reagents (e.g., antibodies) to further drive the sensitivity of the technique at least 2 orders of magnitude lower than the current instrumental limits of ~1-10 ng/mL. Through the use of the ISB-developed human PeptideAtlas, a highly curated proteotypic peptide compendium of all available mass spectrometry data of human proteins as well as other species, efforts are underway for the building of a comprehensive MRMAtlas that contains complete information on the peptide and peptide fragment mass, fragmentation propensity as well as standardized instrumental conditions to employ for successful application of multiplexed quantitative assays. For our proposal, production of small quantities of peptides (~4 peptides per human protein) based on the proteotypic peptides identified through PeptideAtlas and proteotypic peptide predictability software will be used to build a comprehensive MRMAtlas that will contain all the relevant peptide biophysical information, fragmentation information, instrumental conditions, as well as links to some validated assays, all completed in a 2-year time frame. The time is right to create the complete human proteome MRMAtlas. This will undoubtedly accelerate efforts to develop sensitive and reliable assays for early detection, therapy assessment and prognosis evaluation for cancer as well as other human diseases. PUBLIC HEALTH RELEVANCE: The synergistic combination of proteomics, genomics, metabolomics and clinical data will pave the path to personalized medicine by improving diagnostic capabilities, prognostic accuracy, and the development of new, individually tailored therapeutics. We aim to implement state-of-the-art proteomics technology to acquire a unique complete human proteomics compendium for targeting and quantitating any human protein in a multiplexed manner. Our ultimate goal is to integrate this unique targeted proteomics database with genomic and clinical databases, thus providing an invaluable national resource that will expedite current efforts to develop highly sensitive and targeted proteomics-based assays for studying human disease to provide better patient care.

描述（由申请人提供）：个性化医疗将取决于分子特征，以匹配正确的患者正确的药物，首先在临床试验中，然后在临床实践中。个性化医疗是一种新的模式，其中信息技术，科学和临床治疗协同整合，以改善健康和患者福祉。这种方法需要非常大的数据库，涉及分子和临床数据，以便可以主动选择患者进行最合适的治疗。为了实现个体化医疗，关键是开始开发灵敏和可靠的检测方法，以定量检测基因表达、代谢物和蛋白质变化和分布的三体特征。对于蛋白质，我们必须测量稳态或异常分布，以帮助确定当前的健康状况或疾病状态。我们的建议的具体，简单和直接的目标是开发一个完整的蛋白质组为中心的数据库，允许通过使用多反应监测（MRM）的任何人类蛋白质（S）的目标分析。我们将开发和提供一个蛋白质型肽片段数据库，每个人蛋白质编码基因至少有4个肽，并采用经验证的快速准确的MRM质谱分析，以明确识别和定量大量样品中人类蛋白质组的任何蛋白质。根据严格的标准，人类蛋白质编码基因的估计数量为20，332，但可能高达25，000。我们的方法包括建立一个全面的、公开可用的数据库，供用户查询和下载快速实施针对血浆或其他人体组织中感兴趣蛋白质的靶向测定所需的所有信息。此外，该努力提供了用于设计肽-表位捕获试剂（例如，抗体），以进一步驱动该技术的灵敏度比目前的仪器限值约1-10 ng/mL低至少2个数量级。通过使用ISB开发的人类PeptideAtlas（一种高度精心策划的蛋白型肽概要，包含人类蛋白质以及其他物种的所有可用质谱数据），正在努力构建包含完整信息的全面MRMAtlas关于肽和肽片段质量，片段化倾向以及标准化的仪器条件，用于成功应用多重定量测定。对于我们的提议，基于通过PeptideAtlas和蛋白质型肽可预测性软件鉴定的蛋白质型肽生产少量肽（每个人蛋白质约4个肽）将用于构建全面的MRMAtlas，其将包含所有相关肽生物物理信息、片段化信息、仪器条件以及与一些经验证的测定的链接，所有这些均在2年时间范围内完成。现在是时候创建完整的人类蛋白质组MRMAtlas了。这无疑将加速开发用于癌症以及其他人类疾病的早期检测、治疗评估和预后评估的灵敏和可靠的测定方法的努力。 公共卫生相关性：蛋白质组学、基因组学、代谢组学和临床数据的协同组合将通过提高诊断能力、预后准确性和开发新的个性化治疗方法，为个性化医疗铺平道路。我们的目标是实施最先进的蛋白质组学技术，以获得一个独特的完整的人类蛋白质组学纲要，以多路复用的方式靶向和定量任何人类蛋白质。我们的最终目标是将这个独特的靶向蛋白质组学数据库与基因组和临床数据库相结合，从而提供宝贵的国家资源，这将加快目前的努力，开发高灵敏度和靶向蛋白质组学为基础的检测方法，用于研究人类疾病，以提供更好的患者护理。