Complete Human Peptide- and MRM-Atlas

描述（由申请人提供）：个性化医疗将首先在临床试验中，然后在临床实践中，依靠分子特征来匹配合适的患者和合适的药物。个性化医疗是信息技术、科学和临床治疗协同结合以改善健康和患者福祉的一种新范式。这种方法需要异常庞大的数据库，涉及分子和临床数据，以便患者可以主动选择最合适的治疗方法。为了实现个性化医疗，关键是开始开发敏感和可靠的检测方法，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态或疾病状态。我们提出的具体、简单和直接的目标是开发一个完整的以蛋白质组为中心的数据库，以便通过使用多反应监测（MRM）对任何感兴趣的人类蛋白质进行靶向分析。我们将开发并提供一个蛋白质型肽片段数据库，每个人类蛋白质编码基因至少4个肽，并通过经过验证的快速准确的基于MRM的质谱分析，明确地识别和量化大量样品中人类蛋白质组的任何蛋白质。根据严格的标准，人类蛋白质编码基因的数量估计为20332个，但可能高达25000个。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的蛋白质的靶向测定所需的所有信息。此外，这项工作为设计肽表位捕获试剂（如抗体）提供了一个经过验证的蛋白型肽数据库，以进一步推动该技术的灵敏度至少比目前的仪器限制低2个数量级~1-10 ng/mL。通过使用isb开发的人类肽图谱，这是一个高度整理的蛋白质型肽汇编，包含所有可用的人类蛋白质和其他物种的质谱数据，正在努力建立一个全面的MRMAtlas，包含肽和肽片段质量的完整信息，碎片化倾向以及标准化的仪器条件，用于成功应用多重定量分析。根据我们的建议，基于通过PeptideAtlas和proteotypic peptide可预测软件鉴定的蛋白型肽生产少量肽（每个人类蛋白约4个肽）将用于构建一个全面的MRMAtlas，该MRMAtlas将包含所有相关的肽生物物理信息、片段信息、仪器条件以及一些验证分析的链接，所有这些都将在2年内完成。创造完整的人类蛋白质组MRMAtlas的时机已经成熟。毫无疑问，这将加速开发敏感可靠的检测方法，用于癌症和其他人类疾病的早期检测、治疗评估和预后评估。

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.