Many eukaryotic cell types can polarize in response to an external gradient of chemoattractant. The ability to establish an internal compass that points in a precise direction is essential for yeast cells to mate, axons to find their way in the developing nervous system, and cells in the innate immune system to find and kill invading pathogens. Misregulation of cell migration is intimately involved in human disease, such as atherosclerosis and cancer metastasis. Understanding how biological networks dynamically control chemotactic responses is a key step towards developing targeted interventions in pathological conditions. Many of the components and interactions within neutrophil chemotaxis networks have been identified. However, it is not known how basic properties of chemotaxis emerge from detailed molecular descriptions of these networks. Our long term goals are to understand: 1) how dynamic polarization responses are generated by signaling networks;2) which properties of polarity are essential for guiding efficient motility;3) what general mechanisms are employed in diverse motile cells to regulate precise and efficient motility. Here, we propose to study how dynamic polarization and motility responses are generated by signaling networks in human neutrophils.
Our specific aims are to: 1. Identify interactions within the chemotaxis network that control polarization dynamics;2. Model the polarization process;and 3. Identify key polarity phenotypes that are required for guiding efficient motility.

Public Health Relevance

The ability of eukaryotic cells to polarize and migrate in response to external chemical cues is essential for diverse biological processes. While many biochemical components, interactions, and feedbacks within chemotaxis networks have been identified, a major challenge remains to understand how stereotyped polarization and motility responses emerge from these molecular details. Here, we propose to identify sources within human neutrophil signaling networks that control key response properties of chemotaxis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Deatherage, James F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
Zip Code
Coster, Adam D; Wichaidit, Chonlarat; Rajaram, Satwik et al. (2014) A simple image correction method for high-throughput microscopy. Nat Methods 11:602
Wang, Yanqin; Ku, Chin-Jen; Zhang, Elizabeth R et al. (2013) Identifying network motifs that buffer front-to-back signaling in polarized neutrophils. Cell Rep 3:1607-16
Zhang, Elizabeth R; Wu, Lani F; Altschuler, Steven J (2013) Envisioning migration: mathematics in both experimental analysis and modeling of cell behavior. Curr Opin Cell Biol 25:538-42
Houk, Andrew R; Jilkine, Alexandra; Mejean, Cecile O et al. (2012) Membrane tension maintains cell polarity by confining signals to the leading edge during neutrophil migration. Cell 148:175-88
Orchard, Robert C; Kittisopikul, Mark; Altschuler, Steven J et al. (2012) Identification of F-actin as the dynamic hub in a microbial-induced GTPase polarity circuit. Cell 148:803-15
Jilkine, Alexandra; Angenent, Sigurd B; Wu, Lani F et al. (2011) A density-dependent switch drives stochastic clustering and polarization of signaling molecules. PLoS Comput Biol 7:e1002271
Ku, Chin-Jen; Wang, Yanqin; Pavie, Benjamin et al. (2010) ON IDENTIFYING INFORMATION FROM IMAGE-BASED SPATIAL POLARITY PHENOTYPES IN NEUTROPHILS. Proc IEEE Int Symp Biomed Imaging 14-17:1029-1032
Slack, Michael D; Martinez, Elisabeth D; Wu, Lani F et al. (2008) Characterizing heterogeneous cellular responses to perturbations. Proc Natl Acad Sci U S A 105:19306-11
Altschuler, Steven J; Angenent, Sigurd B; Wang, Yanqin et al. (2008) On the spontaneous emergence of cell polarity. Nature 454:886-9
Marco, Eugenio; Wedlich-Soldner, Roland; Li, Rong et al. (2007) Endocytosis optimizes the dynamic localization of membrane proteins that regulate cortical polarity. Cell 129:411-22

Showing the most recent 10 out of 11 publications