In the post-genomic era, quantitative modeling is essential for understanding critical cell functions such as cell movement, cell signaling and cell division. Traditional models of cellular processes often rely on biochemical descriptions of enzymatic events, with no information regarding biomaterial properties or the role of mechanical forces in regulating biochemistry. However, mechanical forces often have a profound influence on biochemistry, and can lead to reorganizations of biological matter and open new biochemical pathways. Improved understanding of cellular force generation and regulation is a goal of this proposal. In particular, we focus on the bacterial systems and ask how forces are generated in the bacterial cytokinetic ring (Z-ring), and how forces influence the observed geometric shape of the bacterial cell. Quantitative models of cell wall growth are proposed. Connections between genetic components and the observed cell shape are investigated using a combination of modeling and experiments. In addition, we propose that the contraction of the Z-ring is driven by lateral interaction between FtsZ filaments. This mechanism does not rely on chemical energy derived from GTP hydrolysis. We propose to test this idea using single molecule and fluorescence imaging experiments. The results of this proposal will build foundations for understanding cell cycles in both prokaryotic and eukaryotic cells, and elucidate the role of mechanics in guiding cell morphogenesis, cell movement and biological functions in general. PHS 398/2590 (Rev. 06/09) Page 1 Continuation Format Page.

Public Health Relevance

Disease-causing microbes that have become resistant to drug therapy are an increasing public health problem. The recent discovery of several bacterial cytoskeletal proteins with shape-defining function provides new molecular targets for anti-bacterial treatments. This proposal seeks to understand the molecular mechanisms behind the prokaryotic cell cycle, develop models to open new strategies to combat pathogens, and reveal principles for the engineering of beneficial microbes. PHS 398/2590 (Rev. 06/09) Page 1 Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM075305-07
Application #
8304157
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Brazhnik, Paul
Project Start
2005-05-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
7
Fiscal Year
2012
Total Cost
$363,458
Indirect Cost
$108,986
Name
Johns Hopkins University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Sun, Sean X (2014) How accurately can a single receptor measure ligand concentrations? Biophys J 106:778-9
Koride, Sarita; He, Li; Xiong, Li-Ping et al. (2014) Mechanochemical regulation of oscillatory follicle cell dynamics in the developing Drosophila egg chamber. Mol Biol Cell 25:3709-16
Aw Yong, Koh Meng; Zeng, Yu; Vindivich, Donald et al. (2014) Morphological effects on expression of growth differentiation factor 15 (GDF15), a marker of metastasis. J Cell Physiol 229:362-73
Li, Bo; Sun, Sean X (2014) Coherent motions in confluent cell monolayer sheets. Biophys J 107:1532-41
Stroka, Kimberly M; Jiang, Hongyuan; Chen, Shih-Hsun et al. (2014) Water permeation drives tumor cell migration in confined microenvironments. Cell 157:611-23
Wu, Pei-Hsun; Giri, Anjil; Sun, Sean X et al. (2014) Three-dimensional cell migration does not follow a random walk. Proc Natl Acad Sci U S A 111:3949-54
Si, Fangwei; Busiek, Kimberly; Margolin, William et al. (2013) Organization of FtsZ filaments in the bacterial division ring measured from polarized fluorescence microscopy. Biophys J 105:1976-86
Stukalin, Evgeny B; Aifuwa, Ivie; Kim, Jin Seob et al. (2013) Age-dependent stochastic models for understanding population fluctuations in continuously cultured cells. J R Soc Interface 10:20130325
Jiang, Hongyuan; Sun, Sean X (2013) Cellular pressure and volume regulation and implications for cell mechanics. Biophys J 105:609-19
Harland, Ben; Walcott, Sam; Sun, Sean X (2011) Adhesion dynamics and durotaxis in migrating cells. Phys Biol 8:015011

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