Dynamics and Bifurcations of Population Structures Induced by Cell Cycle Feedback

描述（由申请人提供）：群体、密度或效率感知，以及其他形式的细胞间通信，已被发现影响许多在生物学、医学和人类健康中重要的生理过程。在酵母中，我们已经证明了非局部形式的细胞周期依赖反馈可以产生振荡的种群密度。在广泛的模型中观察到的数学结果，无论有无随机性，都表明这种现象是稳健的。当细胞周期某一阶段的细胞（G0,G1，S,G2，M）通过代谢物和/或信息素与另一阶段的细胞交流时，观察到这种现象，其结果是后一阶段的细胞经历了生长速度的提前和/或延迟。发展或滞后的结果是人口密度变得多模式和集群化。（想想红绿灯是如何产生成群的汽车的。）实验数据支持这样一种观察，即这种形式的反馈产生了伪同步的细胞群，它们在细胞周期中步调一致。我们之前的工作表明，细胞周期内信号传导和响应区域的大小和位置以及细胞年龄会影响涌现集群的整数。这些因素表明，细胞周期的几何形状比反馈的明确形式和强度更有影响力。通过(1)狭隘地关注涉及密度依赖和细胞周期几何的反馈现象学模型，以及(2)与建模和分析紧密耦合的测量，我们将在理解群集种群现象方面取得进展，并在此背景下为分支理论奠定基础，该理论描述了群集的数量如何能够并将如何响应外部和遗传变异。振荡种群密度可用于实验室和临床，以延长细胞周期同步或降低蛋白质纯化的成本。从生物分子和生物标志物的诊断测量到肿瘤进展的代谢研究，几乎任何涉及增殖细胞群体的检测都可以发现细胞周期依赖性。能够预测和解卷积人口结构影响的模型可能在系统生物学和生物医学中很有用。公共卫生相关性：个体微生物、病原体和肿瘤细胞的行为受到生长和分裂过程的影响。当在群体中观察时，通常情况下，这种变异会影响测试和实验的结果。种群内的变异可能受到种群成员之间交流的影响。因此，生长和分裂过程的模型以及它们如何受到交流的影响对于正确解释测试和实验是很重要的

DESCRIPTION (provided by applicant): Quorum, density or efficiency sensing, as well as other forms of inter-cellular communication, have been found to impact many of the physiological processes that are important in biology, medicine and human health. Working in yeast we have shown that cell cycle dependent feedback of a non-local form can produce an oscillating population density. The mathematical results, observed across a wide range of models, with and without randomness, suggest that the phenomena is robust. The phenomenon is observed when cells in one part of the cell cycle (G0,G1,S,G2,M) communicate with cells in another via metabolites and/or pheromones, with the consequence that the later population experiences advances and/or delays in their growth rate. The outcome of the advances or delays is that the population density becomes multi-modal and clustered. (Consider how traffic lights produce clusters of cars.) Experimental data support the observation that feedback of this form produces clusters of pseudo-synchronized cells that traverse the cell cycle in unison. Our prior work shows that the size and location of signaling and responsive regions within the cell cycle, and cell age, influences the integer number of emergent clusters. These factors suggests a picture in which the geometry of the cell cycle is more influential than the explicit form and strength of the feedback. By (1) focusing narrowly on phenomenological models of feedback that involve density dependence and the geometry of the cell cycle, and (2) tightly coupling measurement with modeling and analysis, we will make progress toward understanding the phenomenon of clustered populations and lay the foundations of a bifurcation theory in this setting that describes how the number of clusters can and will respond to external and genetic variation. Oscillating population density can be exploited in the laboratory and the clinic to prolong cell cycle synchrony or to reduce the cost of protein purification. Cell cycle dependence can con found virtually any assay involving populations of proliferating cells, from diagnostic measurements of bio molecules and biomarkers to metabolic studies of tumor progression. Models that can predict and de convolve the effects of population structure are likely to be useful across systems biology and biomedicine. PUBLIC HEALTH RELEVANCE: The behavior of individual microorganisms, pathogens and tumor cells is influenced by the process of growth and division. When observed in populations, as is normal the case, this variation can influence the outcome of tests and experiments. The variation within a population can be influenced by communication among members of the population. Therefore, models of the process of growth and division and how they are effected bv communication is important for the correct interpretation of tests and experiments