Cancer Proteome Center at Washington Univ, Univ of North Carolina & Boise State

华盛顿大学、北卡罗来纳大学癌症蛋白质组中心

• 批准号: 8323218
• 负责人: XIAN CHEN
• 金额: $ 218.56万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-22 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323218
• 关键词: Address; Affinity; Antibodies; Automobile Driving; Award; Bioinformatics; Biological; Biological Assay; Biological Markers; Biometry; Blood; Blood specimen; Cancer Biology; Cancer Diagnostics; Clinical; Clinical Data; Collection; Complex; Critical Pathways; Data; Development; Development Plans; Diagnosis; Diagnostic; Disease; Early Diagnosis; Early treatment; Epigenetic Process; Epitopes; Frequencies; Gene Dosage; Genes; Genome; Genomics; Goals; Growth; Human; Immunoassay; Incidence; Individual; Institution; Instruction; Knowledge; Label; Lead; Life; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Metabolism; Methods; Minor; Mus; Mutation; Normal Range; North Carolina; Organ; Pathway interactions; Patients; Pattern; Peptide antibodies; Peptides; Phase; Plasma; Point Mutation; Post-Translational Protein Processing; Property; Protein Databases; Proteins; Proteome; Proteomics; Publishing; RNA Splicing; Recurrence; Research; Research Infrastructure; Resolution; Resources; Route; Sampling; Sampling Studies; Sensitivity and Specificity; Shotguns; Somatic Cell; Somatic Mutation; Statistical Models; System; Technology; TimeLine; Tissues; Translating; Translations; Validation; Variant; Washington; Xenograft Model; Xenograft procedure; advanced disease; base; cancer genome; cancer genomics; clinical application; clinical practice; data management; experience; genome sequencing; instrumentation; interest; loss of function mutation; malignant breast neoplasm; meetings; mortality; multiple reaction monitoring; mutant; operation; peripheral blood; programs; protein aminoacid sequence; tool; tumor

DESCRIPTION 4 OVERVIEW OF THE PROPOSED PROTEOMIC CHARACTERIZATION CENTERS 4 1. DISCOVERY UNIT - BIOMARKER DISCOVERY 11 2. VERIFICATION UNIT - BIOMARKER VERIFICATION 16 A. ADMINISTRATIVE CORE - INTERNAL MANAGEMENT COMMITTEE (IMC) 21 B. TECHNOLOGY/PLATFORM DEVELOPMENT PLAN 22 C. BIOINFORMATICS/BIOSTATISTICS 25 D. HUMAN SAMPLES/STUDIES 28 SPECIAL EMPHASIS PANEL ROSTER DESCRIPTION (provided by applicant): DESCRIPTION (provided by applicant): Biomarkers are unique, detectable signatures of cancer that are vital to early diagnosis and treatment. The causes of many cancers are somatic mutations in critical pathways that serve organ growth and metabolism. For over a decade there have been intense proteomic efforts to find biomarkers with clinical utility. There are thousands of published studies and thousands of candidate biomarkers of unknown value for the management of cancer. With the advent of whole genome sequencing, the challenge and immense potential value of characterizing the cancer proteome the readout of the genome-is unfolding. A new paradigm is therefore emerging -"genome-out" directed proteomics. In this application, we propose a comprehensive, blood-based, protein biomarker discovery and verification pipeline that addresses biomarker discovery by starting where the cancer biology begins: with the driving somatic mutations. In the discovery phase, we will use information about recurrent genomic mutations in cancer (i.e. those that occur with a greater than 5% incidence in any given cancer) that are identified by ongoing whole-genome sequencing efforts to focus our collection and analyses of high-throughput, quantitative proteomic data on samples provided by the NCI CPTC in concert with unique resources such as comprehensively sequenced "human in mouse" breast cancer xenografts. Proteomic analyses will include a multiplicity of high-resolution, current and advanced proteomics methods that can characterize intact proteins, massively complex peptide mixtures and protein modifications to elucidate the proteomic facade of cellular pathways and networks. Bioinformatic tools with rigorous statistical models will be applied to meet the challenges of querying the genome directly with proteomic data (proteogenomics). This will provide the orthogonality that cancer genomics requires to biologically validate copy number alterations, point mutations, splice variants, and the complex biological effects from loss of function mutations and epigenetic changes and translate these findings into actionable clinical information. With this melding of proteomic and genomic knowledge, clinically and biologically informed decisions will be made to select candidate biomarkers. The properties of each candidate will be verified by demonstrating an ability of the biomarker assay to reliably distinguish between blood samples taken from healthy individuals from those accrued from patients with cancer. RELEVANCE (See instructions): While early diagnosis can lead to treatments to eliminate a malignancy before the lethal phase, there are presently few clinically viable diagnostics that can be used as a reliable marker for the need for early intervention. Therefore, the goal of this project is to assist the CPTC in discovering new biomarkers, verifying their clinical applicability, and ultimately, helping translate selected biomarkers into clinical practice to reduce mortality from cancer.

说明4 拟议的蛋白质组学特征中心概述4 1.发现单位-生物标记物发现11 2.验证单元--生物标志物验证16 A.行政核心--内部管理委员会(IMC)21 B.技术/平台发展计划22 C.生物信息学/生物统计学25 D.人体样本/研究28 特别强调小组名册 描述(由申请者提供)：描述(由申请者提供)：生物标志物是癌症的独特、可检测的特征，对早期诊断和治疗至关重要。许多癌症的原因是服务于器官生长和新陈代谢的关键途径的体细胞突变。十多年来，蛋白质组学一直在努力寻找具有临床实用价值的生物标记物。有数千项已发表的研究和数千个对癌症管理具有未知价值的候选生物标记物。随着全基因组测序的到来，表征癌症蛋白质组的挑战和巨大的潜在价值-基因组读出-正在展开。因此，一种新的范式正在出现--“基因组输出”导向的蛋白质组学。在这项应用中，我们提出了一个全面的、基于血液的蛋白质生物标记物发现和验证管道，该管道从癌症生物学开始的地方解决生物标记物的发现问题：从驱动体细胞突变开始。在发现阶段，我们将使用正在进行的全基因组测序工作确定的癌症中反复发生的基因组突变(即在任何给定癌症中发生的发病率超过5%的突变)的信息，将我们对高通量、定量蛋白质组数据的收集和分析集中在NCI CPTC与独特资源(如全面测序的“人在鼠”乳腺癌异种移植)提供的样本上。蛋白质组学分析将包括多种高分辨率、当前和先进的蛋白质组学方法，这些方法可以表征完整的蛋白质、大规模复杂的多肽混合物和蛋白质修饰，以阐明细胞路径和网络的蛋白质组学表面。具有严格统计模型的生物信息学工具将被应用于应对直接用蛋白质组数据(蛋白质组学)查询基因组的挑战。这将提供癌症基因组学所需的正交性，以从生物学上验证拷贝数改变、点突变、剪接变异以及因功能突变和表观遗传学改变而产生的复杂生物学效应，并将这些发现转化为可操作的临床信息。随着蛋白质组和基因组学知识的融合，临床和生物知情的决定将做出选择候选生物标记物。将通过展示生物标记物分析可靠地区分健康人的血液样本和癌症患者的血液样本的能力来验证每个候选者的属性。 相关性(见说明)：虽然早期诊断可以导致在致命阶段之前消除恶性肿瘤的治疗，但目前几乎没有临床可行的诊断方法可以用作需要早期干预的可靠标志。因此，该项目的目标是帮助CPTC发现新的生物标记物，验证其临床适用性，并最终帮助将选定的生物标记物转化为临床实践，以降低癌症死亡率。