The response of the actin cytoskeleton in cells to external and internal stimuli is a crucial component of cell migration decisions. Assembly of the cytoskeleton is crucial for force generation and directed motion, while disassembly is crucial for maintaining a high density of free monomers to be used in focused polymerization. Migration is controlled by a complex signaling network which begins with cell-surface receptors at the upstream end, and involves actin-binding proteins that interact directly with actin at the downstream end. The actin-binding proteins control key elementary processes such as filament branching, severing, and depolymerization. Central to the cellular signaling network are the Rho GTPases, small signaling proteins which have GTPase activity. The proposed work develops quantitative simulation methods for predicting the response of the actin cytoskeleton to changes in activity of actin binding proteins. These methods will be combined with mathematical modeling of signaling modules involving the Rho GTPAses to predict cell migration behavior as a function of changes in signaling pathways and chemical treatments. The theoretical predictions will be tested by in vitro experiments. Because aberrant behavior of the actin cytoskeleton is a feature of both cancer and many bacterial diseases, the type of understanding that is gained from these studies can have broad clinical impact. The results of the research will be disseminated to a broad audience by two vehicles: Saturday morning public lectures in the Washington University department of physics, and the University City Science Advisory Council (UCSAC). The Saturday morning lecture series has been in place for approximately a decade, and interdisciplinary topics such as biophysical modeling of cell motion are warmly welcomed. The audience for these lectures typically numbers a hundred or more, representing a broad cross-section of neighborhoods around the University. Professor Carlsson has given several lectures in this series during the past five years, and intends to continue at approximately this pace. UCSAC, an organization of roughly twenty St. Louis area scientists and other concerned individuals, works to enhance the quality of science education in the University City public schools. Professor Carlsson, currently president of this organization, will work to provide a dedicated summer student program and to expand its science club support.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM086882-04
Application #
8112608
Study Section
Special Emphasis Panel (ZGM1-CBCB-5 (BM))
Program Officer
Deatherage, James F
Project Start
2008-08-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$240,321
Indirect Cost
Name
Washington University
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wang, Xinxin; Galletta, Brian J; Cooper, John A et al. (2016) Actin-Regulator Feedback Interactions during Endocytosis. Biophys J 110:1430-43
Holmes, William R (2014) An efficient, nonlinear stability analysis for detecting pattern formation in reaction diffusion systems. Bull Math Biol 76:157-83
Carlsson, Anders E; Bayly, Philip V (2014) Force generation by endocytic actin patches in budding yeast. Biophys J 106:1596-606
Simon, Cory M; Vaughan, Emily M; Bement, William M et al. (2013) Pattern formation of Rho GTPases in single cell wound healing. Mol Biol Cell 24:421-32
Tania, Nessy; Condeelis, John; Edelstein-Keshet, Leah (2013) Modeling the synergy of cofilin and Arp2/3 in lamellipodial protrusive activity. Biophys J 105:1946-55
Edelstein-Keshet, Leah; Holmes, William R; Zajac, Mark et al. (2013) From simple to detailed models for cell polarization. Philos Trans R Soc Lond B Biol Sci 368:20130003
Mata, May Anne; Dutot, Meghan; Edelstein-Keshet, Leah et al. (2013) A model for intracellular actin waves explored by nonlinear local perturbation analysis. J Theor Biol 334:149-61
Dasanayake, Nilushi L; Carlsson, Anders E (2013) Stress generation by myosin minifilaments in actin bundles. Phys Biol 10:036006
Marée, Athanasius F M; Grieneisen, Verônica A; Edelstein-Keshet, Leah (2012) How cells integrate complex stimuli: the effect of feedback from phosphoinositides and cell shape on cell polarization and motility. PLoS Comput Biol 8:e1002402
Holmes, W R; Carlsson, A E; Edelstein-Keshet, L (2012) Regimes of wave type patterning driven by refractory actin feedback: transition from static polarization to dynamic wave behaviour. Phys Biol 9:046005

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