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.

这个项目是为了开发一种前所未有的研究蛋白质组学的工具--蛋白质的集合构成了所有生命形式的分子机制。基因是这种细胞机制的分子前体；基因是编码这些蛋白质在细胞内如何构建的模板。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，它使得破译人类基因组本身成为可能。蛋白质组学技术还没有出现类似的进步。这背后的事实是，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。然后，这种基因扩增使他们能够整体进行直接的分析。蛋白质没有类似的分子扩增过程。事实上，健康和疾病中的关键过程通常只由细胞内蛋白质分子的几个副本决定。因此，只有在逐个分子研究蛋白质的情况下，才能在生物学和医学方面取得根本性进展。在这项工作中确定了一种实现这一目标的实用方法，并提出了组装用于此类分析的新型仪器。研究团队已经确定了一条通往这些目标的独特技术路线，其中连接了三个关键要素。第一，完整蛋白质和蛋白质复合体的单分子分析。这是基于该团队之前发明的两种新方法-纳米机械质谱学和惯性成像。第二，微波频率腔光机械。这使得对关键的纳米机械设备进行超灵敏的测量成为可能，甚至可以达到检测的量子力学极限。第三，最先进的高分辨率天然质谱学。这使得对完整(未分段)蛋白质和蛋白质复合体的研究成为可能。这三个组件将被组装成一个单一的混合仪器，以实现一种新的多物理方法来进行单蛋白质分析，从而克服所有当前方法的限制。它为自动化、高通量的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，最终可能被广泛传播的是技术。对单个细胞进行深入的蛋白质组学分析将对生物学研究、临床医学和药物开发产生重大影响。令人惊讶的是，没有其他技术能够实现这一点。拟议的工作将是高度跨学科的，汇集了跨越物理、工程、化学、生物和数学的研究人员的努力。该项目高度协作和丰富的研究环境将为参与其更广泛努力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在学术界和工业界为生物和医学研究提供对该仪器的长期访问。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。