Widely Distributed Software for Using Mass Spectrometry to Identify Glycans

描述（由申请人提供）：在过去的50年里，我们对人类生物学和疾病的知识有了巨大的增长，这主要是由于分子水平的进步。也许最熟悉的例子是通过DNA测序来研究基因的能力。但同样重要的是通过了解基因的蛋白质产物来研究基因的功能。研究蛋白质最常用的工具是通过质谱法进行蛋白质鉴定。其广泛使用的关键是20世纪90年代开发的软件，如SEQUEST和Mascot，用于从质谱中自动识别蛋白质。现在人们认识到，如果不考虑蛋白质是如何修饰的，就不能理解蛋白质的功能。也许所有修饰中最重要的是糖的添加，即糖基化。所有蛋白质中至少有50%是糖基化的，这种修饰在疾病中的作用已经得到了牢固的确立。但糖基化的研究目前仅限于少数实验室。关键的瓶颈之一是软件——用于从质谱中识别聚糖的类似程序，如SEQUEST和Mascot。这样的软件确实以研究形式存在。我们建议采用一个叫做漫画家的版本，并改进其功能和性能，使其能够在非常广泛的实验室中使用。为此，我们将首先直接与一组规模较小但种类繁多的研究小组合作，使该软件成为他们日常协议的一部分。然后，我们将通过多种渠道开始更广泛的分销，包括利用现有的美国国立卫生研究院资助的功能性糖组学和复杂碳水化合物研究中心联盟。漫画家的关键组件已经存在——它们包括峰选择，软件重新校准，自动生成卡通，以及用于判断聚糖（糖）如何解释光谱中的峰的评分功能。与少数实验室一起工作，我们将确定如何设计和改进这些组件，以创建易于使用且通常有用的软件。这样的软件是扩大能够检测和测量糖基化的研究人员队伍的基本要求，而增加这个队伍反过来又需要更充分地了解糖基化及其在人类疾病中的作用。

DESCRIPTION (provided by applicant): Our knowledge of human biology and disease has increased tremendously in the past 50 years, primarily due to advances at the molecular level. Perhaps the most familiar example is the ability to study genes via DNA sequencing. But equally important is the study of the function of genes by understanding their protein products. The most general tool for studying proteins has become protein identification via mass spectrometry. A key to its widespread use was the development in the 1990's of software such as SEQUEST and Mascot for automatically identifying proteins from a mass spectrum. It is now recognized that protein function cannot be understood without also considering how proteins are modified. Perhaps the most important of all modifications is the addition of sugars, referred to as glycosylation. At least 50% of all proteins are glycosylated, and the role of such modifications in disease has been firmly established. But the study of glycosylation is currently limited to a small number of laboratories. One of the key bottlenecks is software - analogs of programs like SEQUEST and Mascot for identifying glycans from a mass spectrum. Such software does exist in research form. We propose to take one version, called Cartoonist, and improve its functionality and performance so that it is capable enough to be used in a very wide set of laboratories. We will do this by first working directly with a small but diverse set of research groups to make the software become part of their everyday protocols. Then we will begin wider distribution though multiple channels, including leveraging the existing NIH-funded Consortium for Functional Glycomics and Complex Carbohydrate Research Center. The key components of Cartoonist already exist - they include peak picking, software recalibration, and automatic generation of cartoons, and scoring functions for judging how well a glycan (sugar) can explain the peaks in a spectrum. Working together with a small number of labs, we will determine how to engineer and refine these components to create an easy-to-use and generally useful piece of software. Such software is an essential requirement for expanding the pool of researchers able to detect and measure glycosylation, and increasing the pool is in turn a requirement for a fuller understanding of glycosylation and its role in human disease.