MRI: Development of a Highly-Multiplexed Cavity Optomechanical System for Single-Molecule Mass Spectrometry and Inertial Imaging

MRI：开发用于单分子质谱和惯性成像的高度复用腔光机械系统

• 批准号: 1828787
• 负责人: Michael Roukes
• 金额: $ 61.23万
• 依托单位: California Institute of Technology
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1828787&HistoricalAwards=false
• 关键词: MRI; Development; Highly; Multiplexed; Cavity

This project is to develop an unprecedented instrument for studying proteomics - the collection of proteins constituting the molecular machinery underlying all life forms. Genes are the molecular precursors of this cellular machinery; genes are the templates encoding how such proteins are constructed within cells. A profound technological revolution has recently enabled detailed studies of genomic templates; indeed, it has permitted decoding the human genome itself. Similar advances in technology for proteomics has not occurred. Underlying this is the fact that genomic studies are enabled by making billions of identical copies of individual genes. This gene amplification then enables their straightforward analysis en masse. No similar molecular amplification process exists for proteins. In fact, critical processes in health and disease are often determined by only a few copies of a protein molecule within a cell. Fundamental advances in biology and medicine can therefore only be made if proteins are studied molecule-by-molecule. A practical means for accomplishing this is identified in this effort, and assembly of novel instrumentation for such analyses is proposed. The research team has identified a unique technological path toward these ends that concatenates three key elements. First, single-molecule analysis of intact proteins and protein complexes. This is based on two novel approaches previously invented by this team - nanomechanical mass spectrometry and inertial imaging. Second, microwave-frequency cavity optomechanics. This enables ultrasensitive measurements upon the key nanomechanical devices, down to the quantum-mechanical limits of detection. Third, state-of-the-art high-resolution native mass spectrometry. This enables studies of intact (unfragmented) proteins and protein complexes. These three building-blocks will be assembled into a singular hybrid instrument to enable a new multi-physical approach for single-protein analyses that surmounts the limitations of all current methodologies. It offers realistic prospects for automated, high-throughput protein purification, and for identification of intact protein species. Further it is technology that could ultimately be widely disseminated. Deep proteomic profiling of individual cells will be transformational for biological research, clinical medicine, and pharmaceutical development. Surprisingly, no other technology is poised to enable this. The proposed work will be highly cross-disciplinary in nature, bringing together efforts of researchers spanning physics, engineering, chemistry, biology, and mathematics. This project's highly-collaborative and rich research environment will provide unparalleled opportunities for graduate students and postdocs involved in its broader efforts. The team and the collaborators are committed to providing long-term access to this instrument for biological and medical research - both in academia and industry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目旨在开发一种前所未有的工具来研究蛋白质组学——构成所有生命形式的分子机制的蛋白质的集合。基因是这种细胞机器的分子前身。基因是编码这些蛋白质如何在细胞内构建的模板。最近一场深刻的技术革命使得对基因组模板的详细研究成为可能。事实上，它已经允许解码人类基因组本身。蛋白质组学技术方面尚未出现类似的进步。其背后的事实是，基因组研究是通过制作数十亿个相同的单个基因副本来实现的。这种基因扩增使他们能够直接进行整体分析。蛋白质不存在类似的分子扩增过程。事实上，健康和疾病的关键过程通常仅由细胞内蛋白质分子的几个拷贝决定。因此，只有对蛋白质进行逐个分子的研究，生物学和医学才能取得根本性的进步。在这项工作中确定了实现这一目标的实用方法，并提出了用于此类分析的新型仪器的组装。研究团队已经确定了实现这些目标的独特技术路径，该路径连接了三个关键要素。首先，完整蛋白质和蛋白质复合物的单分子分析。这是基于该团队之前发明的两种新颖方法——纳米机械质谱和惯性成像。二是微波频腔光力学。这使得能够对关键纳米机械设备进行超灵敏测量，直至检测到的量子力学极限。第三，最先进的高分辨率原生质谱仪。这使得能够研究完整（未片段化）的蛋白质和蛋白质复合物。这三个构建模块将被组装成一个单一的混合仪器，从而为单蛋白质分析提供一种新的多物理方法，从而克服所有当前方法的局限性。它为自动化、高通量蛋白质纯化和完整蛋白质种类的鉴定提供了现实的前景。此外，技术最终可以得到广泛传播。单个细胞的深度蛋白质组分析将为生物研究、临床医学和药物开发带来变革。令人惊讶的是，没有其他技术能够实现这一点。拟议的工作本质上是高度跨学科的，汇集了物理、工程、化学、生物学和数学研究人员的努力。该项目高度协作和丰富的研究环境将为参与其更广泛工作的研究生和博士后提供无与伦比的机会。该团队和合作者致力于为学术界和工业界的生物和医学研究提供长期使用该仪器的机会。该奖项反映了 NSF 的法定使命，并通过利用基金会的智力优势和更广泛的评估进行评估，认为值得支持。影响审查标准。