An Ultrasensitive Mass Spectrometry Platform for Comprehensive Analysis of Lipids

描述（由申请人提供）：脂质的特定功能与其化学和物理性质有关，并取决于特定的分子结构。尽管技术进步已经使质谱（MS）成为生物分子分析的重要工具，但脂质位置和立体异构体的明确分配仍然是一项具有根本挑战性的任务。该项目的主要目标是开发一个基于MS的仪器平台，该平台能够在复杂的脂质组学样品中阐明脂质结构， 高通量方式，并具有显著提高的灵敏度和特异性。该分析平台将主要基于三重四极杆质谱仪，该质谱仪经过改装，具有高效臭氧诱导解离（OzID）的能力，用于脂质双键位置异构体鉴定。通过与基于电动离子漏斗的MS接口技术和高分辨率场非对称波形离子迁移谱（FAIMS）技术相结合，其灵敏度、动态范围和测量特异性将显著增强。该FAIMS/OzID MS仪器平台的应用将通过分析2型糖尿病队列的人血浆样本来证明，以实现脂质生物标志物的明确和完整的结构阐明。由此产生的仪器平台预计将在完整脂质的结构鉴定中具有广泛的应用，并将有助于发现和 验证生物医学应用中的脂质生物标志物，以及深入了解不同脂质种类的功能作用。 公共卫生相关性（由申请人提供）：脂质代谢失调与多种病理状况相关，如糖尿病、癌症和传染病。拟议的研究将建立一个新的仪器平台，以帮助明确识别疾病的脂质生物标志物，并提高我们对不同脂质在疾病过程中的功能作用的理解。

DESCRIPTION (provided by applicant): The specific functions of lipids are related to their chemical and physical properties and depend on specific molecular structures. Despite technological advancements that have made mass spectrometry (MS) an essential tool for biomolecule analysis, unequivocal assignment of lipid positional and stereo isomers remains a fundamentally challenging task. The primary goal of this project is to develop a MS- based instrument platform that is capable of elucidating lipid structures in complex lipidomic samples in a high throughput manner and with significantly improved sensitivity and specificity. This analytical platform will be primarily based on a triple quadrupole mass spectrometer modified to have the capability of high efficiency ozone induced dissociation (OzID) for lipids double bond positional isomer identification. Its sensitivity, dynamic range and measurement specificity will be significantly enhanced by integrating with electrodynamic ion funnel-based MS interface technology and high resolution field asymmetric waveform ion mobility spectrometry (FAIMS) technology. The applications of this FAIMS/OzID MS instrument platform will be demonstrated by analyzing human plasma samples of a type 2 diabetes cohort to achieve unambiguous and complete structural elucidation of lipid biomarkers. The resulting instrument platform is expected to have broad applications in structural identification of intact lipids and will aid discovery and verification of lipid biomarkers in biomedical applications in addition to providing insights into functional roles of diverse lipid species. PUBLIC HEALTH RELEVANCE (provided by applicant): Dysregulated lipid metabolism is associated with a variety of pathological conditions, such as diabetes mellitus, cancer and infectious diseases. The proposed research will build a new instrument platform to aid the unambiguous identification of lipid biomarkers of diseases and improve our understanding of the functional roles of diverse lipids in the disease process.