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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM097017-01
Application #
8082509
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Gindhart, Joseph G
Project Start
2011-05-01
Project End
2015-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
1
Fiscal Year
2011
Total Cost
$223,730
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
Chan, Yee-Hung M; Reyes, Lorena; Sohail, Saba M et al. (2016) Organelle Size Scaling of the Budding Yeast Vacuole by Relative Growth and Inheritance. Curr Biol 26:1221-8
Kamiyama, Daichi; Sekine, Sayaka; Barsi-Rhyne, Benjamin et al. (2016) Versatile protein tagging in cells with split fluorescent protein. Nat Commun 7:11046
Marshall, Wallace F (2015) How Cells Measure Length on Subcellular Scales. Trends Cell Biol 25:760-8
Marshall, Wallace F (2015) Subcellular size. Cold Spring Harb Perspect Biol 7:
Ludington, William B; Ishikawa, Hiroaki; Serebrenik, Yevgeniy V et al. (2015) A systematic comparison of mathematical models for inherent measurement of ciliary length: how a cell can measure length and volume. Biophys J 108:1361-79
Ishikawa, Hiroaki; Marshall, Wallace F (2015) Efficient live fluorescence imaging of intraflagellar transport in mammalian primary cilia. Methods Cell Biol 127:189-201
Avasthi, Prachee; Onishi, Masayuki; Karpiak, Joel et al. (2014) Actin is required for IFT regulation in Chlamydomonas reinhardtii. Curr Biol 24:2025-32
Kannegaard, Elisa; Rego, E Hesper; Schuck, Sebastian et al. (2014) Quantitative analysis and modeling of katanin function in flagellar length control. Mol Biol Cell 25:3686-98

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