Directional cell migration, chemotaxis, underlies leukocyte infiltration, recruitment, trafficking and homing, which are not only required for normal immune responses, but also responsible for many inflammation-related diseases including ischemic reperfusion, atherosclerosis, asthma, and sepsis. In addition, cell migration occurs in embryonic development, wound healing, and tumor metastasis. Our long term goal is to understand the signaling mechanisms by which chemoattractants regulate leukocyte chemotaxis and their roles in inflammation-related diseases models with the mouse primary neutrophil as the model cell. The central hypothesis of this study is that multiple signaling pathways may function together to regulate neutrophil polarization and directionality. The goals of this application are to fully characterize two new signaling mechanisms and elucidate how these signaling pathways regulate neutrophil chemotaxis in vitro and recruitment in vivo. We will use a combination of molecular and cell biological, biochemical, transgenic, proteomic, functional genomic and advanced in vitro and in vivo imaging approaches to accomplish the following specific aims: 1) To elucidate the novel signaling mechanisms by which cofilin phosphorylation, an event underlining actin remodeling, is regulated by chemoattractants via PLC and PI3K in neutrophils and the role of the signaling mechanism in regulating neutrophil polarization and directionality. 2) To investigate the mechanisms by which integrin signaling regulates PIP5K1C polarization, that has important roles in regulating neutrophil chemotaxis and interaction with endothelial cells. 3) To investigate the roles of these chemoattractant signaling pathways and their interactions in neutrophil chemotaxis in vitro and recruitment in vivo.

Public Health Relevance

Cell migration underlies many of biological processes that range from embryonic development to immune responses. It also plays important roles in inflammation that underlies many human diseases. Directional cell migration is regulated by chemoattractants. This research proposal is to understand how directional cell migration is regulated by various signaling pathways activated by chemoattractants. The study may not shed lights into how this fundamental biological process is regulated, but may also provide potential therapeutic targets for treating inflammation-related human diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Kindzelski, Andrei L
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Yale University
Schools of Medicine
New Haven
United States
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Yuan, Qianying; Ren, Chunguang; Xu, Wenwen et al. (2017) PKN1 Directs Polarized RAB21 Vesicle Trafficking via RPH3A and Is Important for Neutrophil Adhesion and Ischemia-Reperfusion Injury. Cell Rep 19:2586-2597
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Hu, Jian; Yuan, Qianying; Kang, Xue et al. (2015) Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled. Nat Commun 6:8205
Gao, Kun; Tang, Wenwen; Li, Yuan et al. (2015) Front-signal-dependent accumulation of the RHOA inhibitor FAM65B at leading edges polarizes neutrophils. J Cell Sci 128:992-1000
Zhao, Yu; Lin, Yuting; Zhang, Honghong et al. (2015) Ubl4A is required for insulin-induced Akt plasma membrane translocation through promotion of Arp2/3-dependent actin branching. Proc Natl Acad Sci U S A 112:9644-9
Taylor, Ashley; Tang, Wenwen; Bruscia, Emanuela M et al. (2014) SRF is required for neutrophil migration in response to inflammation. Blood 123:3027-36
Zhang, Yong; Tang, Wenwen; Zhang, Haifeng et al. (2013) A network of interactions enables CCM3 and STK24 to coordinate UNC13D-driven vesicle exocytosis in neutrophils. Dev Cell 27:215-226

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