Decode the chemical language that orchestrates cellular and organismal homeostasis

摘要 新陈代谢是生命的基础，代谢失调在人类多种疾病中起着关键作用 疾病。在所有真核细胞中，区室划分是代谢调节的重要组成部分，并且 代谢途径在不同的细胞器内分开，以产生特定的代谢物库。 然而，不同的细胞器也必须协调工作以协调它们的活动，因为 维持最佳的细胞稳态和机体健康。这种细胞和谐是如何实现的 关键但尚未解决的问题。我认为源自细胞器的特定代谢物可以发挥作用 作为细胞内不同区室之间沟通的信使。尽管代谢组学已 鉴定了数千种代谢物，进一步查明这些“信使”代谢物并了解它们的 监管网络在现有工具下不可行。在这个提案中，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结合起来 （SRS）显微镜。这个新的显微镜平台将让我们第一次能够可视化 活生物体细胞器、细胞和组织之间代谢物的时空动态。 2. 开发一种新的成像/分选微流体系统，用于高通量基因组筛选 亚细胞分辨率。该平台将使我们能够每天使用以下任一方法筛查约 100,000 只动物 以定量和自动方式进行共焦或 SRS 显微镜检查。 基于这两项技术创新，我的目标是阐明溶素介导的通讯关系 与细胞核和线粒体，以及破译微生物-宿主线粒体通讯网络。 这些研究将为代谢物介导的通讯系统提供新的概念理解 它们在协调细胞和有机体内平衡中发挥着至关重要的作用。我也期待发现创新 治疗代谢病理学和促进健康老龄化的营养保健目标。总之，该项目将 产生有关小分子化学成像、功能代谢组学和高通量的新见解 基因组学，将对代谢、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.