This proposal is focused on defining the cellular mechanisms that regulate key aspects of human eosnophilbiology, including cell sensitization (priming), chemotaxis, survival and proinflammatory/cytotoxic activities.Eosinophil recruitment and activation are characteristic of airway disorders such as allergic disease, andthese cells exhibit multiple effector activities that contribute to the tissue damage and fibrosis associated withasthma. In this regard, interleukin-5 (IL-5) and related cytokines are critical for modulating eosinophildegranulation, migration, gene expression, and viability. Also, low levels of IL-5-family cytokines induce theenhanced responsiveness of eosinophils to a variety of secondary agents, such as chemoattractants.Although this priming process is important for eosinophil biology, the associated signaling events are not wellunderstood. However, we are uniquely positioned to carefully dissect the role of specific signaling events inmodulating blood and airway eosinophil function. Capabilities enabling this research include: a) Routineaccess to large numbers of highly purified human blood and airway eosinophils. b) Our ongoing identificationof key signaling molecules mediating IL-5 and chemoattractant action in blood and airway eosinophils, e.g:,Ras, the MAP kinases (ERKs 1 and 2), the transcriptional regulators STATs 3 and 5, the beta-arrestinadaptor molecules, and the survival-associated kinase Pim-1. c) Our development of essential molecular andpharmacological methods for analyzing cytokine/chemoattractant signaling in human eosinophils. Theseabilities allow us to test the hypothesis that eosinophil regulation by IL-5 involves the aforementionedsignaling molecules, and that their regulation is important for priming blood eosinophils to becomeresponsive to chemoattractants. The following Aims are proposed: 1) Define the mechanisms of IL-5-mediated priming of chemoattractant-induced events in human blood eosinophils using the activation of theMAP kinases (ERK1/ ERK2) as a cellular marker. 2). Determine the biological relevance of IL-5-dependentactivation of specific receptor/signaling complexes (Ras/ERK, tyrosine kinases, Deta-arrestins) and theintegrity of membrane microdomains in the control of blood and airway eosinophil function. 3) Test theconcept that Jak-STAT-dependent pathways are linked to IL-5-mediated regulation of human eosinophilpriming and function, including Pim-1 expression,.cell survival and chemoattractant-induced responses.
| Tomasini-Johansson, Bianca R; Mosher, Deane F (2018) Microtiter assays for quantitation of assembly of plasma and cellular fibronectin. Methods Cell Biol 143:157-170 |
| Turton, Keren B; Wilkerson, Emily M; Hebert, Alex S et al. (2018) Expression of novel ""LOCGEF"" isoforms of ARHGEF18 in eosinophils. J Leukoc Biol 104:135-145 |
| Bernau, Ksenija; Leet, Jonathan P; Esnault, Stephane et al. (2018) Eosinophil-degranulation products drive a proinflammatory fibroblast phenotype. J Allergy Clin Immunol 142:1360-1363.e3 |
| Stallings, Nancy R; O'Neal, Melissa A; Hu, Jie et al. (2018) Pin1 mediates A?42-induced dendritic spine loss. Sci Signal 11: |
| Moon, Hyung-Geun; Kim, Seung-Jae; Jeong, Jong Jin et al. (2018) Airway Epithelial Cell-Derived Colony Stimulating Factor-1 Promotes Allergen Sensitization. Immunity 49:275-287.e5 |
| Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J et al. (2018) Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J Leukoc Biol 104:69-83 |
| Johansson, Mats W; Kelly, Elizabeth A; Nguyen, Christopher L et al. (2018) Characterization of Siglec-8 Expression on Lavage Cells after Segmental Lung Allergen Challenge. Int Arch Allergy Immunol 177:16-28 |
| Evans, Michael D; Esnault, Stephane; Denlinger, Loren C et al. (2018) Sputum cell IL-1 receptor expression level is a marker of airway neutrophilia and airflow obstruction in asthmatic patients. J Allergy Clin Immunol 142:415-423 |
| Esnault, Stephane; Hebert, Alexander S; Jarjour, Nizar N et al. (2018) Proteomic and Phosphoproteomic Changes Induced by Prolonged Activation of Human Eosinophils with IL-3. J Proteome Res 17:2102-2111 |
| Bortnov, Valeriu; Annis, Douglas S; Fogerty, Frances J et al. (2018) Myeloid-derived growth factor is a resident endoplasmic reticulum protein. J Biol Chem 293:13166-13175 |
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