Almost all eukaryotic cells use actins for multiple vital processes. Cells move, divide, organize their interior, and establish and maintain their shape with the help of actins filaments. Repeated, identical subunits similar across cell types make up these filaments. Despite the common nature of the filaments, cells co-opt them for multifarious tasks with a spectrum of proteins to nucleate, cap, sever, branch, cross-link, and move along them. This work aims both (i) to understand how cells employ actins for specific tasks and (ii) to push our understanding of the actins system towards a physical picture expressed by predictive mathematical models. This study focuses on fission yeast as a model eukaryotic cell. The proposed approach combines mathematical modeling, image analysis, and experimental biology to study how cells organize actins. Two hypotheses form the basis of the study. First, that cross-linking proteins aid the formation of a ring that divides the cytoplasm during the final step of division. Second, that nucleating proteins and severing proteins act in concert with confinement to organize actins into cables. The study proposes to test these hypotheses by (i) extracting relevant quantities from micro- scope images of these structures, (ii) building mathematical models of these structures emphasizing measurable quantities, and (iii) collaborating with experimentalists to subject these models to rigorous challenges. The image analysis uses novel tools, such as tools for automated filament and filament-network tracking, developed in collaboration with computer scientists. The mathematical modeling makes use of a combination of discrete and continuum approaches to dynamical systems informed by experimental parameters. The experimental chal- lenges come in collaboration with Jian-Qiu Wu's lab and in the form of genetic manipulations, pharmacological treatments, and fluorescence microscopy. Every aspect of the study leads to a mechanistic understanding of the actins cytoskeleton and its roles that would underpin future cancer and health research based on an advanced understanding of cellular function.

Public Health Relevance

This project uses mathematical modeling, image analysis, and experimental biology to study the actins cy- toskeleton, a dynamic structure underlying the growth and division of all human cells. If successful, this basic science would underpin future cancer and health research based on an understanding of cellular function.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098430-02
Application #
8448643
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Gindhart, Joseph G
Project Start
2012-03-23
Project End
2016-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
2
Fiscal Year
2013
Total Cost
$262,376
Indirect Cost
$93,018
Name
Lehigh University
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
808264444
City
Bethlehem
State
PA
Country
United States
Zip Code
18015
McMillen, Laura M; Vavylonis, Dimitrios (2016) Model of turnover kinetics in the lamellipodium: implications of slow- and fast- diffusing capping protein and Arp2/3 complex. Phys Biol 13:066009
Merlini, Laura; Khalili, Bita; Bendezú, Felipe O et al. (2016) Local Pheromone Release from Dynamic Polarity Sites Underlies Cell-Cell Pairing during Yeast Mating. Curr Biol 26:1117-25
Zhang, Dan; Bidone, Tamara C; Vavylonis, Dimitrios (2016) ER-PM Contacts Define Actomyosin Kinetics for Proper Contractile Ring Assembly. Curr Biol 26:647-53
Bendezú, Felipe O; Vincenzetti, Vincent; Vavylonis, Dimitrios et al. (2015) Spontaneous Cdc42 polarization independent of GDI-mediated extraction and actin-based trafficking. PLoS Biol 13:e1002097
Vitriol, Eric A; McMillen, Laura M; Kapustina, Maryna et al. (2015) Two functionally distinct sources of actin monomers supply the leading edge of lamellipodia. Cell Rep 11:433-45
Tang, Haosu; Bidone, Tamara C; Vavylonis, Dimitrios (2015) Computational model of polarized actin cables and cytokinetic actin ring formation in budding yeast. Cytoskeleton (Hoboken) 72:517-33
Heisler, David B; Kudryashova, Elena; Grinevich, Dmitry O et al. (2015) ACTIN-DIRECTED TOXIN. ACD toxin-produced actin oligomers poison formin-controlled actin polymerization. Science 349:535-9
Xu, Ting; Vavylonis, Dimitrios; Tsai, Feng-Ching et al. (2015) SOAX: a software for quantification of 3D biopolymer networks. Sci Rep 5:9081
Xu, Ting; Vavylonis, Dimitrios; Huang, Xiaolei (2014) 3D actin network centerline extraction with multiple active contours. Med Image Anal 18:272-84
Bidone, Tamara C; Tang, Haosu; Vavylonis, Dimitrios (2014) Dynamic network morphology and tension buildup in a 3D model of cytokinetic ring assembly. Biophys J 107:2618-28

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