Measuring Lipid Flux By Ultra High Resolution Mass Spectrometry

通过超高分辨率质谱测量脂质通量

基本信息

  • 批准号:
    10796725
  • 负责人:
  • 金额:
    $ 14.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-05 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

Project Summary: Many human diseases are caused by a dysregulation of lipid metabolism, including atherosclerosis, cancer, neurodegeneration, diabetes, and fatty liver. The development of effective treatments for lipid related disorders is hinder by a lack of modern in vivo biochemistry techniques for studying lipid metabolism. The overall goal of this proposal is to develop tools and protocol to measure the rates of lipid biosynthesis and remodeling by stable isotope labeling with sensitivity comparable to radio-isotope tracing with the specificity and broad coverage of modern mass spectrometry based lipidomics. This is enabled by an ultra-high resolution orbitrap mass spectrometer I developed in collaboration of Thermo Scientific, now commercially available as the Lumos 1M. This instrument has sufficient resolution to resolve the natural abundance 13C from a tracer isotope, for example 2H, in intact lipid ions. By resolving the dominant natural abundance ions from tracer isotopes will improve the signal to noise ratio by at least 2 orders of magnitude (1:1 vs >1:100) and increase the dynamic range. This advancement will allow in vivo analysis of lipid metabolism to study a variety of disease, and will ultimately lead to lipid fluxomics analysis that is translatable to human studies. By measuring lipid flux in patients we will be able to directly studying the progression of metabolic syndrome, potentially circumventing the need for animal models, and measure the effectiveness of therapies and interventions. To facilitate the development and widespread implementation of this technology, I will address the fundamental roadblocks to adapting this technology. Firstly, the commercial instrument is engineered for proteomics applications, in particular the electrospray ionization source. By working with the manufacturer and translating my lipidomics experience to this new platform I will overcome these issue. Secondly, I will develop novel data collection approaches for both chromatography and direct infusion based applications to accommodate the long transient time and coalescence issues associated with ultra-high resolution resonance based mass spectrometry. Thirdly, software tools will be developed to extract ultra-high resolution data in a time efficient manner, convert the data to physically interpretable parameters, and map data onto biochemical pathways. Lastly, I will develop protocols and platforms for stable isotope labeling by deuterium labeled water (D2O) and other isotope labeled metabolic tracers in mouse models of metabolic syndrome relevant to my lab’s research program studying the mechanism for fat accumulation. By accomplishing these aims this technology will be accessible to the biomedical research community. My multi-disciplinary training in engineering, physical, analytical and biochemistry, and mouse genetics makes me well-suited to develop this technology and the lipid centric research environment at UT Southwestern is the ideal location for the initial application.
项目总结: 人类的许多疾病都是由脂代谢失调引起的,包括动脉粥样硬化, 癌症、神经变性、糖尿病和脂肪肝。脂类相关疾病有效治疗方法的研究进展 缺乏研究脂质代谢的现代体内生物化学技术,阻碍了疾病的发生。这个 这项提案的总体目标是开发工具和方案来测量脂质生物合成和 稳定同位素标记重塑的敏感性与放射性同位素示踪法相当 以及基于现代质谱学的脂质组学的广泛报道。这是由超高的 我与Thermo Science合作开发的分辨率轨道质谱仪,现已商业化 提供Lumos 1M。这台仪器有足够的分辨率来分辨天然丰度13C 从示踪同位素,例如2H,在完整的脂离子中。通过分解主要的自然丰度离子 示踪同位素将使信噪比提高至少两个数量级(1:1比1:100),并且 增加动态范围。这一进展将使脂代谢的体内分析能够研究 多种疾病,并最终将导致脂流体学分析,这是可翻译为人类研究。通过 通过测量患者的脂质流量,我们将能够直接研究代谢综合征的进展, 潜在地规避了对动物模型的需求,并衡量了治疗和 干预措施。 为了促进这项技术的发展和广泛应用,我将在 适应这项技术的根本障碍。首先,商业票据的设计是为了 蛋白质组学应用,特别是电喷雾电离源。通过与制造商和 将我的脂质组学经验转化到这个新平台上,我将克服这些问题。其次,我会发展 用于基于层析和直接输液的应用的新数据收集方法 适应与超高分辨率共振相关的长瞬变时间和合并问题 基于质谱学。第三,将开发软件工具来提取超高分辨率的数据 以节省时间的方式,将数据转换为物理上可解释的参数,并将数据映射到生化 小路。最后,我将开发稳定同位素的氚标记水标记的协议和平台。 (D2O)和其他同位素标记的代谢示踪剂在与我实验室相关的代谢综合征小鼠模型中的应用 研究脂肪堆积机制的研究计划。通过实现这些目标,这项技术 将向生物医学研究社区开放。我在工程方面的多学科训练, 物理、分析和生物化学以及老鼠遗传学使我非常适合开发这项技术 德克萨斯大学西南分校以脂质为中心的研究环境是最初应用的理想地点。

项目成果

期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)

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Matthew Alvin Mitsche其他文献

Matthew Alvin Mitsche的其他文献

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{{ truncateString('Matthew Alvin Mitsche', 18)}}的其他基金

Measuring Lipid Flux By Ultra High Resolution Mass Spectrometry
通过超高分辨率质谱法测量脂质通量
  • 批准号:
    10027699
  • 财政年份:
    2020
  • 资助金额:
    $ 14.3万
  • 项目类别:
Measuring Lipid Flux By Ultra High Resolution Mass Spectrometry
通过超高分辨率质谱测量脂质通量
  • 批准号:
    10683133
  • 财政年份:
    2020
  • 资助金额:
    $ 14.3万
  • 项目类别:
Measuring Lipid Flux By Ultra High Resolution Mass Spectrometry
通过超高分辨率质谱法测量脂质通量
  • 批准号:
    10470178
  • 财政年份:
    2020
  • 资助金额:
    $ 14.3万
  • 项目类别:
Measuring Lipid Flux By Ultra High Resolution Mass Spectrometry
通过超高分辨率质谱法测量脂质通量
  • 批准号:
    10251244
  • 财政年份:
    2020
  • 资助金额:
    $ 14.3万
  • 项目类别:
Determining the Function of PNPLA3 Utilizing Metabolomics and Stable Isotope Labe
利用代谢组学和稳定同位素标记确定 PNPLA3 的功能
  • 批准号:
    8743229
  • 财政年份:
    2013
  • 资助金额:
    $ 14.3万
  • 项目类别:
Determining the Function of PNPLA3 Utilizing Metabolomics and Stable Isotope Labe
利用代谢组学和稳定同位素标记确定 PNPLA3 的功能
  • 批准号:
    9128645
  • 财政年份:
    2013
  • 资助金额:
    $ 14.3万
  • 项目类别:

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