Modeling and Analysis of the Flagellar Length Control System

鞭毛长度控制系统的建模与分析

• 批准号: 9065592
• 负责人: Wallace Marshall
• 金额: $ 30.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9065592
• 关键词: Address; Affect; Animal Model; Attention; Back; Biological Models; Carrier Proteins; Cells; Cellular biology; Chemicals; Chlamydomonas; Cilia; Computer Simulation; Coupled; Cytoplasmic Protein; Data; Data Analyses; Data Set; Defect; Diffuse; Diffusion; Disease; Ensure; Equilibrium; Feedback; Flagella; Genes; Genetic; Geometry; Health; Hydrocephalus; Image; Image Analysis; Individual; Injection of therapeutic agent; Kinesin; Lead; Length; Life; Marshal; Measurement; Measures; Methods; Microtubules; Modeling; Molecular; Mutation; Non-linear Models; Organelles; Patients; Performance; Photobleaching; Polycystic Kidney Diseases; Regulation; Role; Shapes; Signal Transduction; Speed; Structure; System; Testing; Time; Time Series Analysis; Work; base; cell motility; disabling symptom; fluid flow; genetic manipulation; kinetosome; live cell imaging; particle; quantitative imaging; research study

 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.

 细胞调节其细胞器大小的方法是细胞生物学中一个基本的未回答的问题。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驱动蛋白的运动，称为鞭毛内运输（IFT），这种运输也需要在组装后保持纤毛长度。IFT在纤毛组装中的中心作用，结合IFT中的扰动可以导致纤毛相关疾病的事实，已经将注意力集中在调节IFT活性的机制上。我们已经使用了定量活细胞图像分析表明，IFT颗粒注入到鞭毛的速度取决于鞭毛的长度，这表明鞭毛长度和IFT注射之间的一些监管联系，但这种监管的机制还不清楚。该提案将使用定量活细胞图像分析和实验扰动相结合，结合建模和非线性时间序列分析方法，测试长度如何调节IFT的特定模型。我们还将整合IFT调节与调节的拆卸和前体合成到一个组合的控制系统模型的基础上三个独立的反馈回路，并使用实验扰动来测试的贡献，个别反馈回路的整体系统性能。我们的工作结合了定量活细胞成像和计算建模与强大的遗传学的单细胞模式生物衣原体探测鞭毛动力学。