Stochastic hybrid systems approach to uncovering cell-size control mechanisms

揭示细胞大小控制机制的随机混合系统方法

• 批准号: 9460644
• 负责人: Abhyudai Singh
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-03 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9460644
• 关键词: Algae; Animals; Bacteria; Behavior; Cell Count; Cell Cycle; Cell Proliferation; Cell Size; Cell division; Cells; Chlamydomonas; Chlamydomonas reinhardtii; Complex; Coupling; Data; Daughter; Disease; Eukaryotic Cell; Event; G1 Phase; Gene Expression; Generations; Genetic; Genome; Goals; Growth; Homeostasis; Human; Hybrids; Individual; Kinetics; Laboratory Organism; Malignant Neoplasms; Mathematics; Measurement; Measures; Mediating; Methods; Modeling; Molecular; Mothers; Noise; Proliferating; Proxy; Research; Series; Study models; System; Systems Analysis; Testing; Time; Variant; Work; Yeasts; analog; assay development; base; blastomere structure; cell growth; cell type; digital; insight; mathematical methods; mathematical model; model development; mutant; novel; protein expression; tool development

Proliferating eukaryotic cells actively maintain size homeostasis by coupling cell size to cell division. To do so cells must integrate analog information (i.e. cell size or a proxy for size) and convert it into a digital "all-ornone" decision to divide. While recent work has provided key insights into size homeostasis strategies in bacteria and yeasts, eukaryotic size control remains poorly understood in animals and other taxa. The project investigates size control in a uniquely advantageous model, the unicellular alga Chlamydomonas reinhardtii (Chlamydomonas), where prolonged growth in the G1 period allows individual cells to grow in size up to thirty-fold. At the end of G1, mother cells undergo a rapid series of alternating genome replications and divisions to produce 2n uniform-sized daughters, where n is the number of division cycles. This cell cycle has features in common with some animal early embryonic cell cycles and is controlled by regulators that have homologs or close analogs in animals. How commitment to division occurs, and how Chlamydomonas cells "count" the correct number of subsequent rapid division cycles to achieve cell size homeostasis has remained a mystery. Deterministic models, when applied to Chlamydomonas, are unable to recapitulate observed cell division behavior because they fail to capture stochastic effects. Our prior studies have found Stochastic Hybrid Systems (SHS) that integrate continuous dynamics with random discrete events, to be a powerful framework for modeling size of individual cells across multiple generations. Preliminary analysis of these systems have led to new mathematical results on the forms of coupling between cell size and timing of division essential for maintaining size homeostasis. Combining SHS based models with single-cell measurements of size and gene expression in wild type and cell-cycle mutants, this study will characterize biomolecular circuits mediating size control in Chlamydomonas.

通过将细胞大小耦合到细胞分裂，积极的真核细胞积极维持大小的稳态。为此，单元格必须整合模拟信息（即细胞大小或大小的代理），并将其转换为数字“全索尼酮”决定以分裂。尽管最近的工作为细菌和酵母中的稳态策略提供了关键的见解，但在动物和其他分类单元中，真核大小的控制仍然很少。该项目研究了一个独特的有利模型中的大小控制，即单细胞藻藻reinhardtii（衣原体），在该模型中，G1时期的延长生长允许单个细胞的大小长达31倍。在G1结束时，母细胞会经历一系列快速的交替基因组复制和分裂，以产生2N均匀大小的女儿，其中N是分裂周期的数量。该细胞周期与某些动物早期胚胎细胞周期具有共同点，并且由具有同源物或近距离类似物的调节剂控制。如何进行分裂的承诺以及衣原体细胞如何“计数”随后的快速分裂周期数量，以实现细胞尺寸的稳态仍然是一个谜。 确定性模型在应用于衣原体时，由于无法捕获随机效应，因此无法概括观察到的细胞分裂行为。我们先前的研究发现，随机动力学与随机离散事件相结合，是对多代单个单元进行建模单个细胞大小的强大框架。对这些系统的初步分析已导致有关细胞大小和分裂时间之间的耦合形式的新数学结果，这对于维持尺寸稳态必不可少。将基于SHS的模型与野生型和细胞周期突变体大小和基因表达的单细胞测量结合在一起，本研究将表征介导衣原体中尺寸控制的生物分子电路。