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

• 批准号: 10458074
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10458074
• 关键词: Aging; Biochemical; Biogenesis; Biological; Cell Proliferation; Cells; Cellular biology; Chemicals; Complex; Data; Diabetes Mellitus; Disease; Eukaryota; Eukaryotic Cell; Foundations; Future; Gene Expression; Gene Expression Regulation; Goals; Growth; Growth and Development function; Health; Individual; Investigation; Knowledge; Machine Learning; Malignant Neoplasms; Mammals; Measurement; Measures; Mediating; Metabolic; Metabolism; Modeling; Organelles; Organism; Output; Pathology; Physiological; Play; Positioning Attribute; Property; Research; Role; Route; Shapes; Site; System; Testing; base; cell growth; cell type; design; flexibility; fungus; genetic manipulation; imaging platform; insight; mathematical model; metabolic profile; metabolomics; new therapeutic target; predictive modeling; programs; public health relevance

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.

项目摘要 也许真核细胞的定义特征是其组织成生化不同的隔室 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，但 细胞如何调节其各种细胞器的拷贝数，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宏伟的一种 细胞生物学的挑战。我的研究计划的目的是发现定量原理 管理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。为了实现这一目标，我的研究策略将沿两个方向进行。在第一个 方向，我将定量确定细胞坐标系统如何与细胞的细胞器动力学 增长需求。具体而言，我将量化并建立一个数学模型 细胞细胞器组成和细胞生长。该模型将从通过通过 使用基于机器学习的高光谱，同时可视化所有主要的代谢细胞器 成像平台，对细胞生长和增殖速率施加化学生物学控制以及遗传 扰动关键的细胞器生物发生，组织和相互作用因素。在第二个方向上，我会 确定细胞坐标系统如何验证细胞器动力学和基因表达以控制代谢 在生长和增殖过程中。我将根据单细胞的细胞器含量和 系统地测量其产物执行的基因表达中的时间相关性 细胞器特异性功能。我将同时测量这些细胞的代谢组学分布 细胞器内容。然后，我将结合这些测量值，以开发一种数学模型 捕获由细胞细胞器介导的基因表达与代谢之间的联系 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实现优势。成功的 沿着这两个方向进行的调查将产生有关如何解开复合物的机械洞察力 细胞器动力学，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了解 增长和发展将为未来的研究奠定严格的基础 塑造其细胞器成分，使生化供应与生理需求相匹配， 多细胞生物在健康中利用可塑性来提供发展的代谢灵活性 它是无数细胞的类型，但也通过允许多种癌症代谢病理的途径， 糖尿病和衰老。