The overall goal of this research is to understand quorum sensing: the process of cell-to-cell communication in bacteria. This application will focus on quorum sensing in two related bacteria: Vibrio cholerae, a major human pathogen and the marine-bacteria Vibrio harveyi. The quorum- sensing systems in these bacteria channel multiple quorum-sensing signals into one signaling circuit. At the heart of this circuit are multiple small regulatory RNAs (sRNAs) that mediate the quorum-sensing switch and allow cells to collectively regulate gene expression. The specific goals of this application are (1) to develop a quantitative model for the quorum sensing circuit in V. cholerae and V. harveyi and (2) to develop a new theoretical framework for analyzing how sensory information is integrated by the Vibrio quorum sensing circuit using analytical tools from engineering and physics. Developing a quantitative model and theoretical framework for analyzing information flow will help answer three fundamental questions. (1) How can the Vibrio quorum-sensing network maintain signal-transduction specificity even when multiple signals are transmitted through a shared pathway? (2) What are the comparative advantages for signaling provided by RNA regulators (as opposed to DNA-binding proteins) in the quorum- sensing circuit? (3) What are the major sources of noise in the quorum-sensing circuit and what is the effect of this noise on signaling properties? Answering these questions will contribute to our understanding of intra- and inter-species communication in bacteria and the principles underlying information processing and signaling-transduction in cellular circuits. From a broad modeling perspective, this research is likely to yield new analytic and quantitative tools for analyzing signal-transduction and information flow in biochemical networks. This research also has important health implications because many pathogens such as cholera (Vibrio cholerae) use quorum sensing to regulate virulence. Thus, a greater understanding of quorum-sensing may lead to novel drugs to control infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Mentored Quantitative Research Career Development Award (K25)
Project #
5K25GM086909-05
Application #
8334578
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Sledjeski, Darren D
Project Start
2008-09-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$131,981
Indirect Cost
$9,413
Name
Boston University
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Harcombe, William R; Riehl, William J; Dukovski, Ilija et al. (2014) Metabolic resource allocation in individual microbes determines ecosystem interactions and spatial dynamics. Cell Rep 7:1104-15
Fisher, Charles K; Mehta, Pankaj (2014) Identifying keystone species in the human gut microbiome from metagenomic timeseries using sparse linear regression. PLoS One 9:e102451
Lang, Alex H; Fisher, Charles K; Mora, Thierry et al. (2014) Thermodynamics of statistical inference by cells. Phys Rev Lett 113:148103
Noorbakhsh, Javad; Lang, Alex H; Mehta, Pankaj (2013) Intrinsic noise of microRNA-regulated genes and the ceRNA hypothesis. PLoS One 8:e72676
Reznik, Ed; Mehta, Pankaj; Segre, Daniel (2013) Flux imbalance analysis and the sensitivity of cellular growth to changes in metabolite pools. PLoS Comput Biol 9:e1003195
Teng, Shu-Wen; Schaffer, Jessica N; Tu, Kimberly C et al. (2011) Active regulation of receptor ratios controls integration of quorum-sensing signals in Vibrio harveyi. Mol Syst Biol 7:491
Teng, Shu-Wen; Wang, Yufang; Tu, Kimberly C et al. (2010) Measurement of the copy number of the master quorum-sensing regulator of a bacterial cell. Biophys J 98:2024-31
Mehta, Pankaj; Gregor, Thomas (2010) Approaching the molecular origins of collective dynamics in oscillating cell populations. Curr Opin Genet Dev 20:574-80
Long, Tao; Tu, Kimberly C; Wang, Yufang et al. (2009) Quantifying the integration of quorum-sensing signals with single-cell resolution. PLoS Biol 7:e68
Mehta, Pankaj; Goyal, Sidhartha; Long, Tao et al. (2009) Information processing and signal integration in bacterial quorum sensing. Mol Syst Biol 5:325

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