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对系统生物学提出了许多挑战，其中之一就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的大小目前是细胞生物学中一个悬而未决的问题。我们将重点放在真核生物鞭毛上，将其作为一个简化的一维大小控制问题，以便于定量测量。我们已经构建了一个粗粒度的模型，用于根据鞭毛组件的周转和运输来控制长度。我们定量分析鞭毛成分在鞭毛内的运输和合成的初步数据促使我们重新评估这个简单的模型。基于这些初步结果，我们建议开发一个新的综合长度控制模型，该模型将考虑一系列拟议的活细胞运输和前体合成的定量测量，并以绿藻衣藻为模型系统。通过将前体合成途径的动力学系统建模和鞭毛内运输的随机建模相结合，我们将开发一个能够做出新预测的模型，特别是关于比例和波动的模型。然后，我们将使用新的实验方法进行模型验证和参数估计，以探索活细胞长度控制系统中的比例、波动和动态。我们将利用衣藻的遗传力量，在定义的改变长度的基因中重复测量和模型回归，使我们能够将模型参数与分子路径和组件联系起来。我们预计，通过完成我们的目标，将拥有第一批完全预测细胞大小控制系统的模型之一，我们希望这将成为细胞结构动力学的系统级分析的范例。 公共卫生相关性： 项目叙事Cilia是一种能动的结构，可以驱动流体流动并感知化学信号。纤毛有缺陷的患者会出现一系列衰弱的症状，包括脑积水和多囊肾病，在某些情况下是纤毛异常短或长的结果。我们的研究将揭示基因如何改变这些结构的长度以确保正常功能。

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. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Cilia are motile structures that drive fluid flows and sense chemical signals. Patients with defects in cilia suffer from a range of debilitating symptoms including hydrocephalus and polycystic kidney disease, in some cases as a result of abnormally short or long cilia. Our study will reveal how genes could alter the length of these structures to ensure normal function.