Bioinformatics Algorithms and Software for Proteomics

蛋白质组学的目标是研究生物体中的所有蛋白质，并正在重塑健康研究和制药行业。蛋白质组学的一个重要应用是发现可用于疾病诊断和个性化药物的蛋白质生物标记物。生物标记物也成为优秀的药物靶点。当今癌症治疗中最活跃的领域之一是抗体-药物结合物，它利用抗体识别癌细胞表面的生物标志物，并将药物特异性地输送到癌细胞。质谱学已经成为蛋白质组学中用于蛋白质表征的主要方法。一个质谱学实验可以产生多达数百万个质谱图。然后，使用复杂的计算机算法来分析数据，并找出蛋白质的同一性、初级序列、翻译后修饰(PTM)、单一氨基酸多态(SAP)以及数量。*我提出的研究计划旨在开发算法和软件工具，以促进利用质谱学进行深入的蛋白质组表征。这些工具中的许多将为蛋白质组学提供新的能力。特别是，这项研究计划的最终长期目标是实现整个蛋白质组测序，其中蛋白质组中所有丰富的蛋白质，包括PTM和SAP，都可以在高通量质谱学实验中从头测序。这一突破可能来自一项联合创新，其中包括对光谱仪的巨大改进，一种新颖的实验设计，以及创新的计算机算法。这一目标的实现将从根本上改变科学家进行生物和健康研究的方式，就像过去20年的基因组测序一样。我的研究小组积累了大量的专业知识，并与质谱仪实验室和行业合作伙伴建立了广泛的合作网络。这使我们在对整个蛋白质组测序目标做出关键贡献方面处于有利地位。这一成功将加强加拿大在国际蛋白质组学研究中的领先地位。蛋白质组测序目标可能会延续到NSERC发现计划拟议的续订期限之后。到拟议的期限结束时，我们希望有一种方法，可以在几分钟内用质谱学对纯化的蛋白质进行常规的重新测序。这已经对整个蛋白质组学领域和制药行业产生了深刻的影响。其他短期目标包括实时PTM和SAP检测、蛋白质定量，以及通过依赖结果的获取使质谱仪变得更智能。这些目标的实现将不可避免地需要许多有才华的研究生的参与。许多HQP将在跨学科的环境中接受培训。我设想他们中的许多人将贡献创新的想法，并最终成长为独立的研究人员。

Proteomics aims to study all proteins in an organism, and is reshaping the health research and pharmaceutical industry. One important application of proteomics is the discovery of protein biomarkers that can be used for disease diagnoses and personalized medicine. The biomarkers also become excellent drug targets. One of the most active areas in cancer treatment today is the antibody-drug conjugates that use an antibody to recognize the biomarkers on the surface of cancer cells, and deliver the drug specifically to the cancer cells.******Mass spectrometry has become the primary method in proteomics for protein characterization. One mass spectrometry experiment can produce up to millions of mass spectra. Then, sophisticated computer algorithms are used to analyze the data and find out the proteins' identities, primary sequences, post-translational modifications (PTM), single amino acid polymorphisms (SAP), as well as quantities.******My proposed research program aims to develop the algorithms and software tools that facilitate the in-depth proteome characterization using mass spectrometry. Many of these tools will enable new capabilities for proteomics. In particular, the ultimate long-term goal of this research program is to enable the whole proteome sequencing, where all abundant proteins in a proteome, including the PTM and SAP, can be sequenced de novo in a high-throughput mass spectrometry experiment. The breakthrough will likely come from a joint innovation that involves a vast improvement of spectrometers, a novel experimental design, and innovative computer algorithms. The achievement of this goal will fundamentally change the way scientists conduct biological and health researches just like how genome sequencing did in the past two decades. My research group has accumulated significant expertise and built a broad collaboration network with mass spectrometry labs and industrial partners. This puts us at a good position in making critical contributions to the whole proteome sequencing goal. The success will strengthen Canada's leading position in the international proteomics research.******The proteome sequencing goal may carry beyond the proposed renewal term of this NSERC Discovery program. By the end of the proposed term, we expect to have a method that can routinely de novo sequence a purified protein with mass spectrometry in minutes. This already has a profound impact to the whole proteomics field and pharmaceutical industry. Other shorter term goals include real-time PTM and SAP detection, protein quantification, as well as making the mass spectrometers smarter by result-dependent acquisition.******The accomplishment of these goals will inevitably require the participation of many talented graduate students. Many HQP will be trained in a cross-disciplinary environment. I envision that many of them will contribute innovative ideas, and grow to be independent researchers in the end.