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.
The ability of eukaryotic cells to polarize and migrate in response to external chemical cues isessential for diverse biological processes. While many biochemical components; interactions; andfeedbacks within chemotaxis networks have been identified; a major challenge remains tounderstand how stereotyped polarization and motility responses emerge from these moleculardetails. Here; we propose to identify sources within human neutrophil signaling networks thatcontrol key response properties of chemotaxis.
|Zhang, Elizabeth R; Liu, Shanshan; Wu, Lani F et al. (2016) Chemoattractant concentration-dependent tuning of ERK signaling dynamics in migrating neutrophils. Sci Signal 9:ra122|
|Langen, Marion; Agi, Egemen; Altschuler, Dylan J et al. (2015) The Developmental Rules of Neural Superposition in Drosophila. Cell 162:120-33|
|Pavie, Benjamin; Rajaram, Satwik; Ouyang, Austin et al. (2014) Rapid analysis and exploration of fluorescence microscopy images. J Vis Exp :|
|Agi, Egemen; Langen, Marion; Altschuler, Steven J et al. (2014) The evolution and development of neural superposition. J Neurogenet 28:216-32|
|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|
|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|
|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|
|Ku, Chin-Jen; Wang, Yanqin; Weiner, Orion D et al. (2012) Network crosstalk dynamically changes during neutrophil polarization. Cell 149:1073-83|
|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|
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