Autoinflammatory syndromes comprise a heterogeneous group of inherited disorders characterized by recurrent episodes of aseptic inflammation involving cells of the innate immune system. A hallmark of these disorders is the abnormal infiltration of neutrophils into tissues, suggesting that defects in neutrophil trafficking or motility may contribute to disease pathogenesis. Critical steps during the inflammatory response include leukocyte polarization and migration in the direction of chemoattractant. The long term goal of our work is to define signaling pathways that regulate neutrophil chemotaxis in vitro, and to understand the implications of these mechanisms to chronic inflammatory disease by using zebraflsh as a model system to examine neutrophil chemotaxis and inflammation in vivo. Knowledge of the basic mechanisms that regulate neutrophil chemotaxis should provide therapeutic targets for autoinflammatory syndromes and other disease states in which inflammation is central to pathogenesis. Recent studies from our laboratory demonstrate that the calcium-dependent protease calpain is critical for neutrophil chemotaxis. Our recent studies also show that the phosphatyidylinositol phosphate kinase, PIPKIgamma, interacts with calpain 2 and is required for chemotaxis. We propose to test the hypothesis that PSTPIP1 and other proteins mutated in autoinflammatory syndromes modulate signaling pathways critical for cell migration and chemotaxis, including a novel pathway mediated by calpain 2 and PIPKIgamma, thereby affecting neutrophil chemotaxis and inflammation in vivo.
Specific Aims : I. Elucidate how calpain 2 and PIPKIgamma regulate neutrophil chemotaxis and inflammation. We propose to test the hypothesis that calpain 2 and PIPKIgamma function in a positive feedback loop that regulates neutrophil chemotaxis and inflammation. II. Examine how PSTPIP1, an adaptor protein mutated in PAPA syndrome, modulates neutrophil chemotaxis and inflammation. We propose to examine the interaction between calpain 2 and PSTPIP1, and its role during neutrophil chemotaxis and inflammation. III. Use zebraflsh as a model system to examine neutrophil chemotaxis and inflammation in vivo. Both targeted and non-targeted approaches will be used to identify key signaling pathways involved in neutrophil chemotaxis and inflammation in vivo. We propose to characterize zebrafish PSTPIP1 and develop disease models of autoinflammation.
| de Oliveira, Sofia; Rosowski, Emily E; Huttenlocher, Anna (2016) Neutrophil migration in infection and wound repair: going forward in reverse. Nat Rev Immunol 16:378-91 |
| Vincent, William J B; Freisinger, Christina M; Lam, Pui-Ying et al. (2016) Macrophages mediate flagellin induced inflammasome activation and host defense in zebrafish. Cell Microbiol 18:591-604 |
| LeBert, D C; Squirrell, J M; Huttenlocher, A et al. (2016) Second harmonic generation microscopy in zebrafish. Methods Cell Biol 133:55-68 |
| Rosowski, Emily E; Deng, Qing; Keller, Nancy P et al. (2016) Rac2 Functions in Both Neutrophils and Macrophages To Mediate Motility and Host Defense in Larval Zebrafish. J Immunol 197:4780-4790 |
| LeBert, Danny C; Squirrell, Jayne M; Rindy, Julie et al. (2015) Matrix metalloproteinase 9 modulates collagen matrices and wound repair. Development 142:2136-46 |
| Huttenlocher, Anna; Smith, Judith A (2015) Neutrophils in pediatric autoimmune disease. Curr Opin Rheumatol 27:500-4 |
| Harvie, Elizabeth A; Huttenlocher, Anna (2015) Non-invasive Imaging of the Innate Immune Response in a Zebrafish Larval Model of Streptococcus iniae Infection. J Vis Exp : |
| Harvie, Elizabeth A; Huttenlocher, Anna (2015) Neutrophils in host defense: new insights from zebrafish. J Leukoc Biol 98:523-37 |
| LeBert, Danny C; Huttenlocher, Anna (2014) Inflammation and wound repair. Semin Immunol 26:315-20 |
| Freisinger, Christina M; Huttenlocher, Anna (2014) Live imaging and gene expression analysis in zebrafish identifies a link between neutrophils and epithelial to mesenchymal transition. PLoS One 9:e112183 |
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