Developing high-throughput IMS-MS and IMS-IMS-MS techniques for glycomics analysi

开发用于糖组学分析的高通量 IMS-MS 和 IMS-IMS-MS 技术

• 批准号: 7887486
• 负责人: DAVID E. CLEMMER
• 金额: $ 30.24万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887486
• 关键词: Address; Amino Acids; Attention; Biological; Biological Markers; Blinded; Buffers; Carbohydrates; Cell physiology; Comparative Study; Complex; Complex Mixtures; Control Groups; Coupled; Data; Data Set; Development; Diagnostic; Digestion; Dimensions; Disease; Disease Marker; Disease Progression; Dysplasia; Electrospray Ionization; Esophageal Adenocarcinoma; Gases; Glycoproteins; Goals; Health; Health Status; Housing; Human; Incidence; Ions; Isomerism; Link; Mass Spectrum Analysis; Methods; Molecular; Patients; Phase; Phenotype; Physiological; Plasma; Polysaccharides; Population Study; Proteins; Protocols documentation; Research; Resolution; Role; Sampling; Shapes; Solid; Source; Spectrometry; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure; System; Techniques; Technology; Testing; Time; Tube; United States; Validation; Work; base; cohort; comparative; cost; design; disease phenotype; insight; ion mobility; ionization; molecular marker; mortality; new technology; novel strategies; polypeptide; prototype; public health relevance; research study; two-dimensional

DESCRIPTION (provided by applicant): The increased incidence of Esophageal Adenocarcinoma (EAC) in the United States over the past two decades represents a significant health challenge. This is especially evident considering the high mortality rate of patients who have undergone treatment for EAC. A current goal of scientific research is to identify molecular markers associated with EAC. Considering the multivariate roles of carbohydrates in cellular processes, one field receiving particular attention is glycomics. A limiting factor for comparative glycomics profiling is the myriad glycan structures postulated to exist in biological samples which present challenges for analytical chemists in the form of component resolution and identification. This is especially problematic for mass spectrometry (MS)-based analytical platforms because isomer resolution cannot be achieved with MS alone. Here we propose the use of ion mobility spectrometry (IMS) techniques combined with MS for the rapid characterization of plasma glycan digests. Specifically, multidimensional IMS (IMS-IMS) methods will be developed to provide the highest efficiency characterization of plasma samples. The combination of IMS-IMS with MS allows for rapid resolution of glycan isomers. This enabling technology allows for high-throughput comparison of hundreds of plasma samples necessary for biomarker validation. As part of the research proposed here, the newly developed technology will be applied to biomarker validation of glycan candidates using a population study of 1000 plasma samples. The work proposed here could have tremendous implications for disease diagnostics as well as the ability to track physiological changes associated with disease progression (or regression resulting from therapy). In addition it is possible that the information-rich datasets will also provide clues into molecular causal mechanisms of disease. PUBLIC HEALTH RELEVANCE: The proposed research will develop ion mobility spectrometry (IMS) techniques coupled with mass spectrometry (MS) for comparative glycomics analyses of human plasma. The new technology provides the greatest ability to resolve glycan isomers and thus correlate changes in specific structures with phenotypic differences. The approach will be used to discover and validate new glycan biomarkers for esophageal adenocarcinoma (EAC).

描述（由申请人提供）：在过去的二十年中，美国食管腺癌（EAC）的发病率增加代表了重大的健康挑战。考虑到接受EAC治疗的患者的高死亡率高死亡率，这一点尤其明显。科学研究的当前目标是确定与EAC相关的分子标记。考虑到碳水化合物在细胞过程中的多元作用，一个引起特殊关注的领域是糖基质。比较糖基因分析的一个限制因素是在生物样品中假定存在的无数聚糖结构，这些结构以组分分辨率和鉴定形式提出了分析化学家面临的挑战。这对于基于质谱（MS）的分析平台尤其有问题，因为单独使用MS无法实现异构体分辨率。在这里，我们提出了使用离子迁移率（IMS）技术与MS结合的使用，以快速表征血浆聚糖消化。具体而言，将开发多维IMS（IMS-IM）方法，以提供血浆样品的最高效率表征。 IMS-IM与MS的组合允许快速解析聚糖异构体。这种启示技术允许对生物标志物验证所需的数百种等离子体样品进行高通量比较。作为此处提出的研究的一部分，新开发的技术将使用1000个血浆样本的人群研究应用于聚糖候选者的生物标志物验证。这里提出的工作可能对疾病诊断以及跟踪与疾病进展相关的生理变化（或治疗导致的回归）的能力具有巨大影响。此外，信息丰富的数据集可能还将为疾病的分子因果机制提供线索。 公共卫生相关性：拟议的研究将开发离子迁移率光谱法（IMS）技术以及质谱法（MS）以进行人血浆的比较糖化分析。新技术提供了解决聚糖异构体，从而将特定结构的变化与表型差异相关的最大能力。该方法将用于发现和验证食管腺癌（EAC）的新聚糖生物标志物。