Panoptic electrochemical probe for next-generation mass spectrometry based-lipidomics

用于基于脂质组学的下一代质谱分析的全景电化学探针

• 批准号: 10478940
• 负责人: Xin Yan
• 金额: $ 37.88万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10478940
• 关键词: Address; Biological; Cardiac development; Cardiovascular Diseases; Cell physiology; Characteristics; Chemicals; Complex; Development; Diabetes Mellitus; Diabetic mouse; Diagnosis; Diagnostic; Disease; Geometry; Heart; Homeostasis; Ions; Isomerism; Length; Lipids; Malignant Neoplasms; Mass Spectrum Analysis; Methods; Molecular; Neurodegenerative Disorders; Organism; Outcome; Pathogenesis; Pathology; Physiological; Play; Positioning Attribute; Prediabetes syndrome; Reaction; Research; Role; Running; Sampling; Specificity; Structure; Structure-Activity Relationship; System; Technology; Vision; base; disease diagnosis; instrumentation; lipid metabolism; lipid structure; lipidome; lipidomics; method development; new technology; next generation; novel; pi bond; programs; response; tool; voltage; western diet

PROJECT SUMMARY/ABSTRACT Lipids play a vital role in maintaining cellular function. Altered lipid metabolism is currently considered a hallmark characteristic of many diseases such as malignancies, neurodegenerative diseases, cardiovascular diseases, and diabetes. This has led to a demand for new technologies with comprehensive capabilities for revealing lipid structure and composition. Such technology is essential for the study of lipid structure-function relationships and the development of methods to diagnose and treat pathologies. Recent efforts in mass spectrometry (MS)-based lipidomics, including ion activation methods and chemical derivatization, have expanded the toolbox for lipid analysis. However, there is no single method at present that is capable of resolving all types of lipid structures since lipids are structurally diverse and often contain mixtures of isomers. The lack of efficient and reliable analytical approaches for discerning lipid isomers in biological samples directly leads to the fact that the physiological roles and functions of lipid isomers remain largely unknown. The central vision of my research program is to address the deficiencies in lipid structural analysis technology using the unique microdroplet electrochemical (ME) methods, which take advantage of voltage-controlled electrochemical derivatization of lipid isomers and the dramatically accelerated rates of electrochemical transformations at microdroplet interfaces to achieve structural elucidation. The proposed voltage-triggered ME reactions will be performed in a modified electrospray emitter taking the form of a probe and using standard commercial MS instrumentation. Derivatized products will generate diagnostic ions specific to particular lipid isomers in tandem mass spectra, allowing characterization of detailed structures. During the next five years, my research group aims to develop ME probes for lipid analysis with particular emphasis on isomer identification and quantification so as to realize the promise of ME as a practical research tool for understanding, diagnosing, and treating diseases. A toolbox of ME reactions will be developed to characterize various lipid isomers including lipid class, acyl chain length, double- bond positions, geometries, and sn(stereospecific numbering)-positions, the key information needed for accurate lipid structure annotation. The ME reactions are diverse and can be triggered by voltage changes, so they will be cascaded into a single system (a panoptic ME probe) to identify lipid structures at all levels of isomer specificity in a single experimental run. The ME probe will be used for studying the lipidome of pre-diabetic mouse heart to reveal the initial lipidomic signature in the heart in response to a Western diet and to define the deleterious effects of lipid isomers on the development of cardiac pathology. The expected outcome of this project is to provide a widely applicable approach with enhanced capabilities in lipid structural analysis, which will uncover structure-function relationships in lipid homeostasis and pathology invisible to current lipid profiling.

项目总结/摘要 脂质在维持细胞功能方面起着至关重要的作用。脂质代谢改变目前被认为是一个标志 许多疾病如恶性肿瘤，神经变性疾病，心血管疾病， 和糖尿病这导致了对具有揭示脂质的综合能力的新技术的需求 结构和组成。这种技术对于脂质结构-功能关系的研究至关重要， 发展诊断和治疗疾病的方法。基于质谱（MS）的最近的努力 脂质组学，包括离子活化法和化学衍生法， 分析.然而，目前没有一种方法能够分辨所有类型的脂质结构 因为脂质在结构上是多样的并且通常含有异构体的混合物。缺乏高效可靠的 用于辨别生物样品中脂质异构体的分析方法直接导致以下事实： 脂质异构体的生理作用和功能在很大程度上仍然未知。我研究的中心观点 该计划是为了解决脂质结构分析技术的缺陷，使用独特的微滴 电化学（ME）方法，其利用脂质的电压控制电化学衍生化 异构体和微滴界面处电化学转化的显著加速速率， 实现结构解析。建议的电压触发ME反应将在修改后的 电喷雾发射器采用探针的形式并使用标准商业MS仪器。衍生化 产品将在串联质谱中产生特定脂质异构体的诊断离子， 详细结构的表征。在接下来的五年里，我的研究小组的目标是开发ME探头 用于脂质分析，特别强调异构体的鉴定和定量，以实现 ME作为理解，诊断和治疗疾病的实用研究工具。我的工具箱 将开发反应来表征各种脂质异构体，包括脂质类别、酰基链长度、双- 键位置、几何形状和sn（立体定向编号）位置，这些都是精确计算所需的关键信息。 脂质结构注释。ME反应是多种多样的，并且可以由电压变化触发，因此它们将 级联到单个系统（全景ME探针）中，以识别所有水平的异构体的脂质结构 在一个单一的实验运行的特异性。ME探针将用于研究糖尿病前期患者的脂质组 小鼠心脏，以揭示心脏中响应于西方饮食的初始脂质组学特征， 脂质异构体对心脏病理学发展的有害作用。预期的结果是， 项目是提供一种广泛适用的方法，具有增强的脂质结构分析能力， 将揭示脂质稳态和病理学中的结构-功能关系，这些关系是目前脂质分析所看不到的。