Modeling and Analysis of the Flagellar Length Control System

描述（由申请人提供）： 摘要 复杂细胞内结构的动力学给系统生物学带来了许多挑战，其中之一是了解调节细胞结构大小的控制系统。细胞如何控制细胞器大小的问题目前是细胞生物学中尚未解答的问题。我们关注真核鞭毛作为一个简化的一维尺寸控制问题，有助于定量测量。我们构建了一个粗粒度模型，用于鞭毛成分周转和运输方面的长度控制。我们定量分析鞭毛内运输和鞭毛成分合成的初步数据使我们重新评估简单模型。基于这些初步结果，我们建议开发一种新的长度控制综合模型，该模型将考虑到活细胞中运输和前体合成的一系列拟议定量测量，使用绿藻衣藻作为模型系统。通过结合前体合成途径的动力系统建模和鞭毛内运输的随机建模，我们将开发一个可以做出新颖预测的模型，特别是在缩放和波动方面。然后，我们将使用新的实验方法进行模型验证和参数估计，以探测活细胞长度控制系统的缩放、波动和动态。我们将通过对改变长度的定义基因的突变体进行重复测量和模型回归来利用衣藻的遗传力量，从而使我们能够将模型参数与分子途径和成分联系起来。我们期望通过完成我们的目标，获得第一个细胞尺寸控制系统的完全预测模型，我们希望它将成为细胞结构动力学系统级分析的范例。

DESCRIPTION (provided by applicant): Abstract The dynamics of complex intracellular structures pose many challenges for systems biology, one of which is to understand the control systems that regulate the size of cellular structures. The question of how cells control organelle size is currently an unanswered question in cell biology. We are focusing on the eukaryotic flagellum as a simplified, one-dimensional size control problem that facilitates quantitative measurement. We have constructed a coarse-grained model for length control in terms of turnover and transport of flagellar components. Preliminary data in which we quantitatively analyze intraflagellar transport and synthesis of flagellar components has caused us to re-evaluate the simple model. Basd on these preliminary results, we propose to develop a new integrated model for length control that will take into account a series of proposed quantitative measurements of transport and precursor synthesis in living cells, using the green alga Chlamydomonas as a model system. By combining dynamical systems modeling of the precusor synthesis pathway and stochastic modeling of intraflagellar transport, we will develop a model that can make novel predictions, particularly with respect to scaling and fluctuations. We will then perform model verification and parameter estimation using new experimental methods to probe scaling, fluctuation, and dynaimcs in the length control system in living cells. We will leverage the genetic power of Chlamydomonas by repeating measurements and model regression in mutants in defined genes that alter length, allowing us to link model parameters with molecular pathways and components. We expect, by completing our aims, to have one of the first fully predictive models for a cellular size control system, which we hope will serve as a paradigm for systems-level analysis of cellular structural dynamics.