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

基本信息

批准号：
10799315
负责人：
Xin Yan
金额：
$ 25万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

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.

项目摘要/摘要脂质在维持细胞功能中起着至关重要的作用。改变脂质代谢目前被认为是标志许多疾病的特征，例如恶性肿瘤，神经退行性疾病，心血管疾病，和糖尿病。这导致了对具有全面功能揭示脂质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的研究至关重要诊断和治疗病理的方法的发展。质谱法（MS）的最新努力脂质组学，包括离子激活方法和化学衍生化，已扩展了脂质的工具箱分析。但是，目前尚无单一方法能够解决所有类型的脂质结构由于脂质在结构上是多样的，并且通常包含异构体的混合物。缺乏高效和可靠的辨别生物样品中辨别脂质异构体的分析方法直接导致这样一个事实，即脂质异构体的生理作用和功能在很大程度上尚不清楚。我的研究的中心愿景计划是使用独特的微螺旋体来解决脂质结构分析技术中的缺陷电化学（ME）方法，它利用了脂质的电压控制电化学衍生物异构体和微核接口上电化学转化的速度急剧加速速率实现结构阐明。提出的电压触发我的反应将在修改后进行电喷雾发射器采用探针的形式并使用标准的商业MS仪器。衍生产品将在串联质谱中生成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。在接下来的五年中，我的研究小组旨在发展我的探测对于脂质分析，特别强调异构体识别和量化，以实现诺言我是理解，诊断和治疗疾病的实用研究工具。我的工具箱将开发反应以表征各种脂质异构体，包括脂质类，酰基链长度，双重异构体债券位置，几何形状和SN（立体编号） - 位置，准确的关键信息脂质结构注释。我的反应是多种多样的，可以通过电压变化触发，因此它们会将级联成单个系统（一个综合ME探针），以识别所有级别的异构体的脂质结构单个实验运行中的特异性。 ME探测器将用于研究糖尿病前的脂质体小鼠心脏以响应西方饮食来揭示心脏中最初的脂肪组签名并定义脂质异构体对心脏病理发展的有害影响。预期的结果项目将提供一种广泛适用的方法，并具有增强的脂质结构分析功能，这将发现脂质稳态和病理学的结构功能关系，这对于当前的脂质分析看不见。