Decode the chemical language that orchestrates cellular and organismal homeostasis

摘要 代谢是生命的基础，代谢失调在多种人类疾病中起着关键作用。 疾病在所有真核细胞中，区室化是代谢调节的重要组成部分， 代谢途径在不同的细胞器内被分离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，以协调其活动， 维持最佳的细胞内稳态和有机体适应性。如何实现这种细胞和谐是一个 关键但未解决的问题。我认为来自细胞器的特定代谢物 作为信使在细胞的不同区域之间进行交流。尽管代谢组学 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 监管网络对于当前的工具来说是不可行的。在这份提案中，我提出了两项技术创新： 1.高光谱受激拉曼散射耦合同位素标记和荧光成像 (SRS)显微镜这个新的显微镜平台将使我们第一次看到 生物体中细胞器、细胞和组织之间代谢物的时空动力学。 2.开发用于高通量基因组筛选的新型成像/分选微流体系统， 亚细胞分辨率该平台将使我们能够使用以下两种方法每天筛选约100，000只动物： 以定量和自动方式进行共聚焦或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联系 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信系统提供新的概念理解， 它们在协调细胞和生物体内平衡中的重要作用。我也希望能发现创新的 用于治疗代谢病理和促进健康衰老的营养药物靶标。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.