Technology Research and Develeopment Project 1: A proteogenomics approach for the discovery of aberrant cancer genes and analyzing antibody repertoires

项目摘要 质谱学的基础是将生物分子分割成更小的碎片，并使用碎片 质量作为鉴定和量化生物分子的指纹。它是一种主导技术， 研究健康和疾病组织中的活性分子，识别蛋白质靶标和天然产物 寻找新的治疗方法。当最初提出的计算质谱学中心(CCMS)是 2007年提交的，由于缺乏足够的计算工具来分析质谱学数据， 关键的瓶颈。在新的实验技术的应用方面取得了巨大的成功，例如 FTMS、ETD、HCD、自上而下的质谱学和许多其他，CCMS的任务仍然是 新一代计算技术的发展及其在开放实验中的应用。在……里面 这项提议，我们将利用我们在计算蛋白质组学不同子领域的最新成果，并将 进一步分支到以前未探索过的MS应用程序。我们将特别关注桥接蛋白质组学 以及采用6个技术研发平台的基因组学技术。 具体地说，我们将(A)应用蛋白质组学方法来发现癌症基因和 分析抗体谱系；(B)对天然抗生素进行排序；(C)通过光谱对光谱数据进行整理 档案和网络；(D)开发鉴定多肽的通用工具；(E)开发自上而下的工具 蛋白质组学；以及，(F)分析多重光谱。这些技术平台是由大量合作的生物医学研究推动的，在这些研究中，CCMS开发的工具的使用对于它们的成功至关重要。这些 研究包括：(A)解开人类疾病中的组蛋白组合密码；(B)蛋白质基因组学 研究口腔微生物组和多细菌感染的方法；(C)检测物种间的化学相互作用；(D)为乙酰组的治疗调节制定系统的方法；(E) 开发单抗和多克隆抗体测序工具；(F)开发乳腺癌疫苗；(G)临床癌症蛋白质组学；(H)发现抗菌素；(I)发现蛋白质组生物标记物 用于癌症患者的药物毒性；以及，(J)确定白内障晶状体中的蛋白质-蛋白质相互作用和翻译后修饰。这些项目需要在广泛的主题上进行三方合作。 包括生物医学科学家、质谱学家和来自不同机构的计算科学家。 CCMS还将培训来自世界各地的学生和实习科学家，学习计算蛋白质组学， 并教育蛋白质组学社区有关现代计算质谱学的知识，以鼓励其 广泛领养。

Project Summary Mass spectrometry is based on fragmenting biological molecules into smaller pieces, and using the fragment masses as a fingerprint for identifying and quantifying bio-molecules. It is the dominant technology for studying active molecules in healthy and diseased tissue, and identifying protein targets and natural products for novel therapeutics. When the initial proposal Center for Computational Mass Spectrometry (CCMS) was submitted in 2007, the lack of adequate computational tools for analyzing mass spectrometry data was the the key bottleneck. With great success in enabling applications of new experimental techniques such as FTMS, ETD, HCD, top-down mass spectrometry, and many others, the mandate of CCMS continues to be the development of next generation computational technologies and to apply them to open experimental. In this proposal, we will capitalize on our recent results in diverse subfields of computational proteomics and will further branch into previously unexplored MS applications. We will focus specifically on bridging proteomics and genomics technologies using 6 technology research and development platforms. Specifically, we will (a) apply proteogenomics approach for the discovery of abberant cancer genes and analyzing antibody repertoires; (b) sequence natural antibiotics; (c) collate spectral data through spectral archives and networks; (d) develop universal tools for peptide identification; (e) develop tools for top-down proteomics; and, (f) analyzing multiplexed spectra. The technology platforms are driven by a multitude of collaborative biomedical studies where the use of CCMS developed tools is essential for their success. These studies include (a) unraveling the combinatorial histone code in human diseases; (b) a proteogenomics approach to studies of oral microbiome and polybacterial infections; (c) detecting inter-species chemical interactions; (d) developing a systems approach towards the therapeutic modulation of the acetylome ; (e) developing tools for monoclonal and polyclonal antibody sequencing; (f) development of breast cancer vaccines; (g) clinical cancer proteogenomics; (h) discovery of lantibiotics; (i) discovering proteomic biomarkers for drug toxicity in cancer patients; and, (j) identifying protein-protein interactions and post-translational modifications in cataractous lens. These projects require three-way collaborative efforts on a wide range of topics involving biomedical scientists, mass spectrometrists, and computational scientists from various institutions. CCMS will also train students and practicing scientists from all over the world in computational proteomics, and educate the proteomics community about modern computational mass spectrometry to encourage its wide adoption.