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

该项目旨在开发一种前所未有的研究蛋白质组学的工具-构成所有生命形式基础的分子机制的蛋白质集合。基因是这种细胞机制的分子前体;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。类似的蛋白质组学技术进步还没有出现。这背后的事实是，基因组研究是通过制作数十亿个相同的个体基因拷贝来实现的。然后，这种基因扩增使其能够直接分析。对于蛋白质，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，生物学和医学的根本性进步只有在蛋白质被逐个分子地研究的情况下才能实现。一个实用的方法来实现这一点，确定在这项工作中，并提出了组装新的仪器进行这种分析。研究团队已经确定了一条独特的技术路径，将三个关键要素串联起来。第一，完整蛋白质和蛋白质复合物的单分子分析。这是基于该团队先前发明的两种新方法-纳米机械质谱法和惯性成像。第二，微波频腔光力学。这使得对关键纳米机械设备的超灵敏测量能够达到量子力学的检测极限。第三，最先进的高分辨率天然质谱。这使得研究完整的（未碎片化的）蛋白质和蛋白质复合物成为可能。这三个构建模块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，用于单蛋白质分析，克服所有现有方法的局限性。它提供了现实的前景，自动化，高通量的蛋白质纯化，并为完整的蛋白质种类的鉴定。此外，最终能够广泛传播的是技术。单个细胞的深度蛋白质组分析将对生物学研究、临床医学和药物开发产生变革性影响。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性质，汇集了研究人员跨越物理，工程，化学，生物学和数学的努力。该项目的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，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.