Modeling and Analysis of the Flagellar Length Control System

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 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.