Vibrational Spectroscopic Imaging to Unveil Hidden Signatures in Living Systems

项目摘要 Cheng团队研究的一个中心主题是关注对生物分子如何 和/或分子组合体在空间和时间中起作用以驱动生命。例如，膜是如何 对神经元的动作电位做出反应在细胞发育或癌症过程中，新陈代谢是如何重塑的 进展？当暴露于药物治疗时，微生物内部的化学物质会发生什么变化？ 探讨这些问题对于诊断和治疗从传染性疾病到 疾病到转移性癌症。为了实现这一使命，程和他的团队发明并应用了高度敏感的 化学成像技术能够揭示各种生命系统中隐藏的特征。最终 目标是实现基于分子的人类疾病的精确诊断和/或治疗。Cheng团队 进一步利用和操纵光子的独特性质来调节细胞的行为。两 重点项目是光解发色团以消除耐药细菌和光声 神经组织在空间上的精确调节。总的来说，凭借工程方面的综合专业知识， 物理、化学、生物、医学和创业，研究团队致力于三个综合 重点：（1）发明无标记光学调制和光谱成像技术，并推动其 物理限制;（2）发现定义细胞状态和功能的分子特征;（3）转换标签- 免费技术和生物学发现转化为基于分子的精确诊断和治疗。 在过去的5年里（2013年至2018年），Cheng及其同事的研究推动了 振动光谱成像在速度、光谱带宽、成像深度和检测灵敏度方面 (for a review，Science，2015，350：aaa 8870）。与此同时，通过合作，Cheng和同事们发现， 定义癌症侵袭性的显著代谢特征（Cell Metabolism 2014），癌细胞干细胞性 (Cell Stem Cell 2017）和抗菌素耐药性（Anal Chem 2017），以及 神经元的膜电压（JPC Lett 2017）。该MIRA提案的总体目标是进一步推动 非线性振动光谱成像平台的边界，以揭示签名， 通过在真实的空间中"观看分子的交响乐"来引发或发展人类疾病， 生命系统中的时间Cheng和他的同事将通过提高两个人的能力来实现这一目标。 互补的振动成像平台，即多重受激拉曼散射显微镜， 红外光热显微镜都是在程实验室发明的，达到单分子检测灵敏度， 100 nm空间分辨率、高速体积标测和深层组织穿透。作为聚焦的 应用程序，该团队将部署开发的技术，以推进对如何 生物细胞在体内发育期间或响应于应激而重新编程其代谢。

Project Summary A central theme of research in the Cheng group is focused on basic understanding of how biomolecules and/or molecular assemblies function in space and time to drive life. For example, how does the membrane respond to the action potential in neurons? How is the metabolism remodelled during cell development or cancer progression? What happens to the chemistry inside a microorganism when exposed to a drug treatment? Answering these questions has broad implications for diagnosing and treating conditions ranging from infectious diseases to metastatic cancers. Towards this mission, Cheng and his team invent and apply highly sensitive chemical imaging technologies that are able to unveil hidden signatures in various living systems. The eventual goal is to enable molecule-based precision diagnosis and/or treatment of human diseases. The Cheng team further harnesses and manipulates the unique properties of photons to modulate the behaviour of cells. Two focused projects are photolysis of chromophores to eradicate drug-resistant bacteria and optoacoustic modulation of neural tissues at ultrahigh spatial precision. Overall, with integrated expertise in engineering, physics, chemistry, biology, medicine and entrepreneurship, the research team is devoted to three integrated thrusts: (1) Inventing label-free optical modulation and spectroscopic imaging technologies and pushing their physical limits; (2) Discovering molecular signatures that define cellular state and functions; (3) Converting label- free technologies and biological discoveries into molecule-based precision diagnosis and treatments. During the past 5 years (2013 to 2018), research by Cheng and co-workers has pushed the boundary of vibrational spectroscopic imaging in terms of speed, spectral bandwidth, imaging depth, and detection sensitivity (for a review, Science, 2015, 350: aaa8870). In parallel, via collaborations, Cheng and co-workers discovered significant metabolic signatures defining cancer aggressiveness (Cell Metabolism 2014), cancer cell stemness (Cell Stem Cell 2017), and antimicrobial resistance (Anal Chem 2017), as well as a spectroscopic indicator of membrane voltage in neurons (JPC Lett 2017). The overarching goal of this MIRA proposal is to further push the boundary of nonlinear vibrational spectroscopic imaging platforms in order to unveil the signatures that underlie initiation or progression of human diseases by “watching the orchestra of molecules” in real space and time inside a living system. Cheng and co-workers will pursue this goal by advancing the capability of two complimentary vibrational imaging platforms, namely multiplex stimulated Raman scattering microscopy and infrared photothermal microscopy both invented in the Cheng lab, to reach single-molecule detection sensitivity, 100-nm spatial resolution, volumetric mapping at high speed, and deep-tissue penetration. As a focused application, the team will deploy the developed technologies to advance the basic understanding of how a biological cell reprograms its metabolism during development in vivo or in response to a stress.