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.

项目概要/摘要 脂质在维持细胞功能中起着至关重要的作用。脂质代谢的改变目前被认为是一个标志 许多疾病的特征，如恶性肿瘤、神经退行性疾病、心血管疾病、 和糖尿病。这导致了对具有揭示脂质综合能力的新技术的需求 结构和组成。这种技术对于研究脂质结构-功能关系和 诊断和治疗病理学方法的开发。基于质谱 (MS) 的最新研究成果 脂质组学，包括离子活化方法和化学衍生化，扩展了脂质的工具箱 分析。然而，目前还没有一种方法能够解析所有类型的脂质结构 因为脂质结构多样并且通常含有异构体的混合物。缺乏高效可靠的 辨别生物样品中脂质异构体的分析方法直接导致了这样一个事实： 脂质异构体的生理作用和功能仍然很大程度上未知。我的研究的中心愿景 该计划旨在利用独特的微滴解决脂质结构分析技术的缺陷 电化学 (ME) 方法，利用脂质的电压控制电化学衍生化 异构体以及微滴界面处的电化学转化速率显着加快 实现结构阐明。所提议的电压触发 ME 反应将在改进的 电喷雾发射器采用探针形式并使用标准商用 MS 仪器。衍生化 产品将在串联质谱中产生特定于特定脂质异构体的诊断离子，从而允许 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探针 用于脂质分析，特别强调异构体鉴定和定量，以实现这一承诺 ME 作为理解、诊断和治疗疾病的实用研究工具。 ME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、双链 键位、几何形状和 sn（立体定向编号）位置，这是准确测量所需的关键信息 脂质结构注释。 ME 反应多种多样，可以通过电压变化触发，因此它们会 级联到单个系统（全景 ME 探针）中，以识别异构体各级的脂质结构 单次实验的特异性。 ME探针将用于研究糖尿病前期的脂质组 小鼠心脏揭示了心脏对西方饮食的反应的初始脂质组学特征，并定义了 脂质异构体对心脏病理学发展的有害影响。本次活动的预期结果 该项目旨在提供一种广泛适用的方法，增强脂质结构分析的能力， 将揭示当前脂质分析中看不见的脂质稳态和病理学中的结构-功能关系。