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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
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Gindhart, Joseph G
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Bhaduri, Sayantan; Ranjan, Nihar; Arya, Dev P (2018) An overview of recent advances in duplex DNA recognition by small molecules. Beilstein J Org Chem 14:1051-1086
Hendel, Nathan L; Thomson, Matthew; Marshall, Wallace F (2018) Diffusion as a Ruler: Modeling Kinesin Diffusion as a Length Sensor for Intraflagellar Transport. Biophys J 114:663-674
Chang, Amy Y; Marshall, Wallace F (2017) Organelles - understanding noise and heterogeneity in cell biology at an intermediate scale. J Cell Sci 130:819-826
Ishikawa, Hiroaki; Marshall, Wallace F (2017) Testing the time-of-flight model for flagellar length sensing. Mol Biol Cell 28:3447-3456
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Marshall, Wallace F (2015) Subcellular size. Cold Spring Harb Perspect Biol 7:
Marshall, Wallace F (2015) How Cells Measure Length on Subcellular Scales. Trends Cell Biol 25:760-768
Ishikawa, Hiroaki; Marshall, Wallace F (2015) Efficient live fluorescence imaging of intraflagellar transport in mammalian primary cilia. Methods Cell Biol 127:189-201

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