Decode the chemical language that orchestrates cellular and organismal homeostasis

摘要 新陈代谢是生命的基础，新陈代谢失调在各种各样的人类中起着关键作用 疾病。在所有真核细胞中，区隔是代谢调节的关键组成部分，并且 代谢途径在不同的细胞器中分离，以产生特定的代谢物池。 然而，不同的细胞器也必须协调工作来协调它们的活动，因为 维持最佳的细胞动态平衡和机体健康。这种细胞和谐是如何实现的 关键但尚未解决的问题。我认为从细胞器中提取的特定代谢物可以 作为信使在细胞中的不同隔间之间进行通信。尽管代谢组学已经 鉴定了数千种代谢物，进一步确定了这些“信使”代谢物，并了解了它们的 监管网络在目前的工具下是不可行的。在这项建议中，我提出了两项技术创新： 1.将同位素标记和荧光成像与高光谱受激拉曼散射相结合 (SRS)显微镜。这个新的显微镜平台将使我们第一次能够可视化 生物体中细胞器、细胞和组织间代谢产物的时空动力学。 2.开发一种新的用于高通量基因组筛选的成像/分选微流控系统 亚细胞分辨率。这个平台将使我们能够每天使用以下两种方法之一来筛选大约100,000只动物 以定量和自动的方式进行共聚焦或SRS显微镜检查。 基于这两项技术创新，我旨在阐明溶血因子介导的沟通联系。 具有细胞核和线粒体，以及破译微生物与宿主线粒体的通讯网络。 这些研究将提供对代谢物介导的通讯系统和 它们在协调细胞和组织的动态平衡方面起着至关重要的作用。我也期待发现创新的 治疗代谢疾病和促进健康衰老的营养靶点。总而言之，这个项目将 在小分子化学成像、功能代谢组学和高通量方面产生新的见解 基因组学，并将对新陈代谢、细胞生物学和衰老生物学领域的研究产生重大影响。

ABSTRACT Metabolism is fundamental to life, and metabolic dysregulation plays a key role in a wide variety of human diseases. In all eukaryotic cells, compartmentation is a crucial component of metabolic regulation, and metabolic pathways are separated within different cellular organelles to generate specific pools of metabolites. However, different cellular organelles also have to work in harmony to coordinate their activities, for maintaining optimal cellular homeostasis and organismal fitness. How this cellular harmony is achieved is a pivotal but unsolved question. I propose that specific metabolites derived from cellular organelles could serve as messengers to communicate between different compartments in the cell. Although metabolomics has identified thousands of metabolites, further pinpointing those “messenger” metabolites and understanding their regulatory network are not feasible with current tools. In this proposal, I propose two technological innovations: 1. Couple isotope-labeling and fluorescence imaging with hyperspectral stimulated Raman scattering (SRS) microscopy. This new microscopy platform will allow us, for the first time to visualize spatiotemporal dynamics of metabolites between organelles, cells and tissues in living organisms. 2. Develop a new imaging/sorting microfluidics system for high-throughput genomic screening with subcellular resolution. This platform will enable us to screen ~100,000 animals per day using either Confocal or SRS microscopy in a quantitative and automatic manner. Based on these two technological innovations, I aim to elucidate lysokine-mediated communication nexus with the nucleus and mitochondria, as well as decipher microbe-host mitochondria communication network. These studies will provide new conceptual understanding of metabolite-mediated communication systems and their crucial roles in orchestrating cellular and organismal homeostasis. I also expect to discover innovative nutraceutical targets for treating metabolic pathologies and promoting healthy aging. Together, this project will yield new insights regarding small molecule chemical imaging, functional metabolomics and high-throughput genomics, and will have high impact on research in the field of metabolism, cell biology and aging biology.