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.

增殖的真核细胞通过将细胞大小与细胞分裂偶联来主动维持大小稳态。要做到这一点，细胞必须整合模拟信息（即细胞大小或大小的代理），并将其转换为数字“全或无”的决定进行分裂。虽然最近的工作提供了关键的见解大小稳态策略在细菌和酵母，真核生物的大小控制仍然知之甚少，在动物和其他类群。该项目研究了一种独特的有利模型，即单细胞莱茵衣藻（Chlamyelium reinhardtii）的大小控制，其中G1期的长时间生长允许单个细胞的大小增长高达30倍。在G1期结束时，母细胞经历一系列快速的交替基因组复制和分裂，产生2n个大小均匀的子细胞，其中n是分裂周期的数量。这种细胞周期与一些动物早期胚胎细胞周期具有共同的特征，并且由在动物中具有同源物或接近类似物的调节剂控制。如何承诺分裂发生，以及衣原体细胞如何“计数”随后的快速分裂周期的正确数量，以实现细胞大小的稳态仍然是一个谜。 确定性模型，当应用于衣原体，是无法概括观察到的细胞分裂行为，因为他们无法捕捉随机效应。我们之前的研究发现，将连续动态与随机离散事件相结合的随机混合系统（SHS）是一个强大的框架，可以对多代个体细胞的大小进行建模。这些系统的初步分析导致了新的数学结果之间的耦合形式的细胞大小和时间的分裂至关重要的维持大小的稳态。结合SHS为基础的模型与野生型和细胞周期突变体的大小和基因表达的单细胞测量，本研究将表征介导衣原体大小控制的生物分子电路。