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The design principles of the eukaryotic cell: uncovering the coordination of systems-level organelle dynamics, metabolism and growth

真核细胞的设计原理：揭示系统级细胞器动力学、代谢和生长的协调

基本信息

批准号：
10673651
负责人：
Arindam Shankar Mukherji
金额：
$ 39.38万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

项目摘要

Project Summary Perhaps the defining feature of the eukaryotic cell is its organization into biochemically distinct compartments known as organelles. While the biochemical functions of individual organelles are often well known, how cells regulate the copy numbers, sizes, and subcellular positions of its diverse organelles in a coordinated fashion and how organelles interact to produce integrated physiological outputs remain one of the grand challenges in cell biology. The goal of my research program is to discover the quantitative principles governing how cells regulate systems-level organelle dynamics to coordinate metabolism, growth, and proliferation. To achieve this goal, my research strategy will proceed along two directions. In the first direction, I will quantitatively determine how cells coordinate systems-level organelle dynamics with cellular growth demands. Specifically, I will quantify and build a mathematical model of the relationship between cellular organelle composition and cell growth. The model will be calibrated from data obtained by simultaneously visualizing all major metabolic organelles using our machine learning-based hyperspectral imaging platform, exerting chemical biological control over cell growth and proliferation rates, and genetically perturbing key organelle biogenesis, organization, and interaction factors. In the second direction, I will determine how cells coordinate systems-level organelle dynamics and gene expression to control metabolism during growth and proliferation. I will categorize single cells according to their organelle content and systematically measure the temporal correlations in their expression of genes whose products execute organelle-specific functions. I will concomitantly measure the metabolomic profile of these cells sorted by organelle content. I will then combine these measurements to develop a mathematical model that quantitatively captures the connection between gene expression and metabolism as mediated by the cell's organelle makeup. I will subsequently test predictions of this model by systematically tuning organelle interaction strengths by modulating the expression of organelle biogenesis factors and organelle contact sites. Successful investigations along these two directions will yield mechanistic insight into how to untangle the complex interdependencies between organelle dynamics, metabolism, and cell growth and proliferation. A systems- level understanding of how organelle composition and interactions coordinate metabolism to control cellular growth and development will lay a rigorous foundation into future investigations into how the cell actively shapes its organelle composition to match biochemical supply with physiological demand through, how this plasticity is leveraged in health by multicellular organisms to provide the metabolic flexibility needed to develop its myriad cell types, but also in disease by allowing for multiple routes to metabolic pathologies in cancer, diabetes, and aging.

项目概要也许真核细胞的定义特征是其组织成生化上不同的区室称为细胞器。虽然单个细胞器的生化功能通常是众所周知的，细胞如何协调地调节其不同细胞器的拷贝数、大小和亚细胞位置时尚以及细胞器如何相互作用以产生综合的生理输出仍然是最重要的问题之一细胞生物学的挑战。我的研究计划的目标是发现定量原理控制细胞如何调节系统级细胞器动力学以协调代谢、生长和增殖。为了实现这个目标，我的研究策略将沿着两个方向进行。在第一个方向，我将定量确定细胞如何协调系统级细胞器动力学与细胞增长需求。具体来说，我将量化并建立一个数学模型来描述之间的关系细胞器组成和细胞生长。该模型将根据获得的数据进行校准使用我们基于机器学习的高光谱同时可视化所有主要代谢细胞器成像平台，对细胞生长和增殖率施加化学生物控制，并从遗传角度扰乱关键细胞器的生物发生、组织和相互作用因素。在第二个方向上，我会确定细胞如何协调系统级细胞器动力学和基因表达来控制新陈代谢在生长和增殖过程中。我将根据细胞器内容对单细胞进行分类系统地测量其产物执行的基因表达的时间相关性细胞器特异性功能。我将同时测量这些细胞的代谢组学特征，按以下顺序排序细胞器含量。然后我将结合这些测量结果来开发一个数学模型，定量地捕捉细胞器介导的基因表达和代谢之间的联系化妆品。随后我将通过系统地调整细胞器相互作用来测试该模型的预测通过调节细胞器生物发生因子和细胞器接触位点的表达来增强优势。成功的沿着这两个方向的研究将产生如何理清复杂问题的机械见解细胞器动力学、新陈代谢以及细胞生长和增殖之间的相互依赖性。一个系统—— 对细胞器组成和相互作用如何协调代谢以控制细胞的水平理解生长和发育将为未来研究细胞如何活跃奠定坚实的基础塑造其细胞器组成，使生化供应与生理需求相匹配，这是如何实现的多细胞生物在健康中利用可塑性来提供发育所需的代谢灵活性它的无数细胞类型，而且还通过允许多种途径导致癌症代谢病理学在疾病中，糖尿病、衰老。