Imaging mass spectrometry at isomeric chemical resolution using gas phase ion/ion reactions

项目总结 分子成像在生物医学研究中起着举足轻重的作用。通过实现生物的可视化 直接在组织中的过程，细胞功能的原位评估可以记录在空间背景下。这个 使用质谱学作为分子成像手段结合了高水平的分子特异性 由质谱仪提供的具有显微成像方法的空间保真度。通过这种方式，成像 质谱学(IMS)提供了组织中广泛的生物分子的无标记图谱 标本。准确识别在发育和功能障碍过程中改变的生化途径 为各种应用设计新的治疗策略的关键一步，例如在糖尿病研究中， 传染病、药物药理学和癌症。然而，在分化方面仍然存在严重的不足 以及在成像质谱学实验中检测到的分子的结构鉴定 组织样本的巨大化学复杂性。未能充分区分和识别这些 化合物导致离子图像由多个具有重叠质量的不同化合物组成。这 分子分布的扭曲图像给成像产生的生化图谱的解释蒙上了阴影 这会妨碍对细胞组成和功能的完整和准确的了解。 这项提议旨在开发方法和仪器，使组织成像达到无与伦比的水平 敏感度、分离度和认同感。这将通过发现和开发 针对脂质和代谢物中特定化学官能团的新型气相离子/离子反应 (具体目标1)。这些反应为分子转化提供了快速而灵活的手段，而不需要 操纵组织样本，可以提高检测下限和更广泛的化学物质 结构信息。开发可重复和定量的离子/离子反应方法将使 从组织中进行可靠的测量(特定目标2)。仪器的发展可以 高通量地进行气相离子/离子反应将使这些转变得以进行 直接在成像质谱学实验中使用(特定目标3)。这些“被动”的画面是可以预见的 以揭示常规成像方式无法获得的空间生化细节。可持续发展 新的分析技术，如在此提出的那些，是至关重要的，以解决日益 复杂的生物学和临床问题。

PROJECT SUMMARY Molecular imaging plays a pivotal role in biomedical research. By enabling the visualization of biological processes directly in tissue, in situ assessments of cellular function can be recorded with spatial context. The use of mass spectrometry as a molecular imaging modality combines the high level of molecular specificity provided by the mass spectrometer with the spatial fidelity of a microscopic imaging approach. By this, imaging mass spectrometry (IMS) provides for the label-free mapping of a wide array of biomolecules in tissue specimens. Accurate identification of the biochemical pathways altered during development and dysfunction is a key step in designing novel treatment strategies for a variety of applications, such as in studies of diabetes, infectious disease, drug pharmacology, and cancer. However, severe deficiencies remain in the differentiation and structural identification of molecules detected during imaging mass spectrometry experiments due to the enormous chemical complexity of tissue samples. The failure to adequately separate and identify these compounds results in ion images consisting of multiple different compounds with overlapping masses. This distorted picture of molecular distributions clouds the interpretation of the biochemical maps produced by imaging mass spectrometry and prevents a complete and accurate understanding of cellular compositions and functions. This proposal aims to develop methods and instrumentation that will enable tissue imaging at unparalleled levels of sensitivity, separation, and identification. This will be achieved through the discovery and development of novel gas-phase ion/ion reactions that target specific chemical functional groups in lipids and metabolites (Specific Aim 1). These reactions offer rapid and flexible means for molecular transformations without manipulating the tissue sample and can result in improved detection limits and more extensive chemical structural information. Developing reproducible and quantitative ion/ion reaction methodologies will enable reliable measurements to be made from tissue (Specific Aim 2). The development of instrumentation that can perform gas-phase ion/ion reactions with high throughput will enable these transformations to be performed directly during imaging mass spectrometry experiments (Specific Aim 3). These ‘reactive’ images are anticipated to reveal spatial biochemical detail unobtainable by conventional imaging modalities. The continual development of new analytical technologies such as those proposed herein is crucial in order to address increasingly complicated biological and clinical questions.