The behavior, adaptability, and survival of organisms, including pathogens or immune system components, depend critically upon the capability to formulate appropriate responses, at different time scales, to fluctuating temporal patterns of environmental cues such as ligand concentrations or stresses. Traditionally, mathematical studies have focused on constant environments and steady-state behaviors, not on naturally occurring signals and transient behavior. The ultimate goal of this work is to investigate, both theoretically and experimentally, the characteristics of biological responses to time-varying signaling and what information is encoded in them. The primary focus will be on the study of invariance with respect to sensory symmetries, with an initial emphasis on fold-change-detection (FCD), a property that confers signaling systems robustness to scale uncertainty. Recent molecular cell biology studies have experimentally discovered FCD behavior in prokaryotic chemotaxis pathways, allowing responses to broad ranges of chemoattractant concentrations, and in the eukaryotic epidermal growth factor ERK and the Wnt signaling pathways, allowing robustness of behavior in the face of large variations in protein abundances.
One aim of this work is to develop new, and to significantly expand existing, theory of FCD and other symmetries.
This aim will involve foundational work in areas of mathematics ranging from control theory to group representations. Broader significance will include new insights in nonlinear dynamics and systems biology, as the properties studied are emergent synthetic behaviors, not explainable easily from the properties of individual chemicals in isolation. A complementary aim is to develop an experimental platform to study transient behaviors, particularly in chemotaxis. New experimental tools will be established, based on microfluidic technology and on molecular level analysis of intracellular signaling (FRET), to afford unprecedented spatiotemporal control of stimuli during measurements and to allow the effective testing of mathematical predictions. Broader significance will be in fostering the development of new microfluidic technology of wide applicability in biology and biomedical engineering.

Public Health Relevance

Chemotaxis plays a key role in bacterial motion, as well as in embryonic morphogenesis, tissue organization, tumor angiogenesis, and wound healing. Activity of the ERK pathway controls cell proliferation, differentiation, and apoptosis. The Wnt signaling pathway plays a role in embryonic patterning and stem cell homeostasis, and its disregulation has been linked to colorectal cancer and hepatocellular carcinoma.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZGM1-CBCB-5 (BM))
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Gindhart, Joseph G
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Rutgers University
Biostatistics & Other Math Sci
Schools of Arts and Sciences
New Brunswick
United States
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Son, Kwangmin; Menolascina, Filippo; Stocker, Roman (2016) Speed-dependent chemotactic precision in marine bacteria. Proc Natl Acad Sci U S A 113:8624-9
Skataric, Maja; Nikolaev, Evgeni V; Sontag, Eduardo D (2015) Fundamental limitation of the instantaneous approximation in fold-change detection models. IET Syst Biol 9:1-15
Prabakaran, Sudhakaran; Gunawardena, Jeremy; Sontag, Eduardo (2014) Paradoxical results in perturbation-based signaling network reconstruction. Biophys J 106:2720-8
Yang, Rong; Jang, Hongchul; Stocker, Roman et al. (2014) Synergistic prevention of biofouling in seawater desalination by zwitterionic surfaces and low-level chlorination. Adv Mater 26:1711-8
Margaliot, Michael; Sontag, Eduardo D; Tuller, Tamir (2014) Entrainment to periodic initiation and transition rates in a computational model for gene translation. PLoS One 9:e96039
Rusconi, Roberto; Garren, Melissa; Stocker, Roman (2014) Microfluidics expanding the frontiers of microbial ecology. Annu Rev Biophys 43:65-91
Yawata, Yutaka; Cordero, Otto X; Menolascina, Filippo et al. (2014) Competition-dispersal tradeoff ecologically differentiates recently speciated marine bacterioplankton populations. Proc Natl Acad Sci U S A 111:5622-7
Shapiro, Orr H; Fernandez, Vicente I; Garren, Melissa et al. (2014) Vortical ciliary flows actively enhance mass transport in reef corals. Proc Natl Acad Sci U S A 111:13391-6
Mayola, Albert; Irazoki, Oihane; Martínez, Ignacio A et al. (2014) RecA protein plays a role in the chemotactic response and chemoreceptor clustering of Salmonella enterica. PLoS One 9:e105578
Billings, Nicole; Rusconi, Roberto; Stocker, Roman et al. (2014) Microfluidic-based Time-kill Kinetic Assay. Bio Protoc 4:

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