Complete Human Peptide- and MRM-Atlas

完整的人类肽和 MRM 图谱

• 批准号: 7938786
• 负责人: LEROY E HOOD
• 金额: $ 230.19万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938786
• 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，首先在临床试验中，然后在临床实践中，将正确的患者与正确的药物相匹配。个性化医疗是信息技术、科学和临床治疗协同整合以改善健康和患者福祉的新范式。这种方法需要异常庞大的数据库，将分子和临床数据相关联，以便可以主动选择患者接受最合适的治疗。为了实现个性化医疗，至关重要的是开始开发灵敏且可靠的检测方法来定量检测基因表达、代谢物和蛋白质变化和分布的三组学特征。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。我们提案的具体、简单和直接目标是开发一个完整的以蛋白质组为中心的数据库，以便通过使用多重反应监测（MRM）对任何感兴趣的人类蛋白质进行有针对性的分析。我们将开发并提供一个蛋白型肽片段数据库，每个人类蛋白质编码基因至少包含 4 个肽，并通过经过验证的快速、准确的 MRM 质谱分析来明确识别和量化大量样品中人类蛋白质组的任何蛋白质。根据严格标准，人类蛋白质编码基因的估计数量为 20,332 个，但也可能高达 25,000 个。我们的方法包括建立一个全面的、公开的数据库，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的蛋白质的靶向测定所需的所有信息。此外，这项工作还提供了一个经过验证的蛋白型肽数​​据库，用于设计肽表位捕获试剂（例如抗体），以进一步提高该技术的灵敏度，比当前约 1-10 ng/ 的仪器极限低至少 2 个数量级。毫升。通过使用 ISB 开发的人类 PeptideAtlas（一个精心策划的蛋白质肽概要，包含人类蛋白质以及其他物种的所有可用质谱数据），正在努力构建一个全面的 MRMAtlas，其中包含有关肽和蛋白质的完整信息。肽片段质量、片段化倾向以及用于成功应用多重定量分析的标准化仪器条件。对于我们的提案，基于通过 PeptideAtlas 和蛋白质肽预测软件鉴定的蛋白质肽生产少量肽（每个人类蛋白质约 4 个肽），将用于构建一个全面的 MRMAtlas，其中包含所有相关的肽生物物理信息、片段化信息、仪器条件以及一些经过验证的分析的链接，全部在 2 年的时间内完成。创建完整的人类蛋白质组 MRMAtlas 的时机已经成熟。这无疑将加速开发灵敏可靠的检测方法，用于癌症及其他人类疾病的早期检测、治疗评估和预后评估。 公共健康相关性：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体化治疗方法，为个体化医疗铺平道路。我们的目标是实施最先进的蛋白质组学技术，以获得独特的完整人类蛋白质组学纲要，以多重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整合，从而提供宝贵的国家资源，这将加快目前开发高度敏感和靶向蛋白质组学检测方法的努力，以研究人类疾病，从而提供更好的患者护理。