Modeling and Analysis of the Flagellar Length Control System

 描述：细胞调节细胞器大小的方法是细胞生物学中一个基本的悬而未决的问题。纤毛和鞭毛由于其简单的一维形状，为研究细胞器大小控制的一般问题提供了一个方便的模型系统。纤毛和鞭毛的组装需要一种基于激动素的运动，称为鞭毛内运输(IFT)，这种运输也是在组装后维持纤毛长度所必需的。IFT在纤毛组装中的核心作用，再加上IFT中的干扰可导致纤毛相关疾病的事实，使人们对IFT活动的调控机制产生了关注。我们使用了定量的活细胞图像分析来表明IFT颗粒以依赖于鞭毛长度的速度被注入鞭毛，这表明鞭毛长度和IFT注入之间存在某种调控联系，但这种调控的机制尚不清楚。这项提议将使用定量活细胞图像分析和实验扰动相结合的方法，结合建模和非线性时间序列分析方法，测试特定的模型，以了解长度如何调节IFT。我们还将把IFT规则与拆卸和前体合成的规则整合到一个基于三个独立反馈回路的联合控制系统模型中，并使用实验扰动来测试单个反馈回路对整体系统性能的贡献。我们的工作将定量活细胞成像和计算建模与单细胞模式生物衣藻的强大遗传学相结合，用于探测鞭毛动力学。

 DESCRIPTION: The means by which cells regulate the size of their organelles is a fundamental unanswered question in cell biology. Cilia and flagella provide a convenient model system to study the general question of organelle size control due to their simple one- dimensional shape. Assembly of cilia and flagella requires a kinesin based motility called intraflagellar transport (IFT), and this transport is also required to maintain ciliary length afte assembly. The central role of IFT in ciliary assembly, combined with the fact that perturbations in IFT can lead to cilia-related diseases, has focused attention on the mechanisms that regulate IFT activity. We have used quantitative live cell image analysis to show that IFT particles are injected into the flagellum at a rate that depends on the flagellar length, suggesting some regulatory linkage between flagellar length and IFT injection, but the mechanism of this regulation is not understood. This proposal will test specific models for how length may regulate IFT using a combination of quantitative live cell image analysis and experimental perturbations, coupled with modeling and nonlinear time series analysis methods. We will also integrate IFT regulation with regulation of disassembly and of precursor synthesis into a combined control system model based on three separate feedback loops, and use experimental perturbations to test the contributions that individual feedback loops make to overall system performance. Our work combines quantitative live cell imaging and computational modeling with the powerful genetics of the unicellular model organism Chlamydomonas for probing flagellar dynamics.