Airway eosinophilia is an important marker of asthma severity, risk of exacerbation, and response to therapy. Based upon the current understanding of the function of eosinophils (EOS), the preliminary data and studies accomplished over the previous funding cycle, form the basis for the hypothesis that EOS play a pivotal role in asthma pathophysiology by enhancing airway inflammation and remodeling. The studies in this PPG renewal application are designed to answer clinically important questions formulated to take maximum advantage of our collective expertise and resources. They will allow us to address critically, comprehensively and interactively the role of EOS in allergic airway inflammation using ex vivo and in vivo experiments in human subjects complemented, as appropriate, by focused use of cell lines and animal models. Project 1 will investigate key EOS functions including promoting IL-17 responses and enhancing fibroblast (Fb) function via expression of SEMA7A, which leads to promoting myoFb differentiation and generation of extracellular matrix (ECM) components. The Th2 skewed environment in the asthmatic airway promotes the expression of periostin, an important marker of allergic inflammation. The proposed studies in Project 2 will determine how this ECM protein interacts with EOS to enhance their survival, mediator release, and response to EOS-active cytokines. Studies will define the requirements for periostin generation in the airway and recognition by the EOS integrin alphaMBeta2. Finally in Project 3, the molecular mechanisms regulating the pro-fibrotic cytokine, TGF-Beta1 signaling in EOS and Fb will be investigated focusing on the role of Pin1 interaction with proximal Smads as well as PI-3-K and Akt. Our group discovered that up-regulation of isomerase Pin1 is an essential step in the TGF-Beta1 signaling pathway and seek to determine how Pin1 influences Smad6 and Smad3 including the role of Akt and PI-3-Kgamma in this process. It can be argued that few other centers, if any, around the world are capable of doing the clinical studies needed to retrieve airway EOS and at the same time have the experience necessary to critically dissect EOS biological functions to the same level of sophistication that our group is capable of doing. The collaborative studies among the three laboratories and the rich clinical research experience will allow us to move back and forth from ex vivo to in vivo experiments to better understand the role of EOS in modulating allergic airway inflammation and remodeling. Given the prominence of eosinophilic inflammation in a significant proportion of severe asthma patients, these advances will have direct implications for the patients most affected by this very common illness.
From these collaborative and integrated approaches, we will unveil novel insights into the pathobiology of asthma, with implications for other illnesses where eosinophils are known to be an important participant These advances will be crucial to focusing the quest for the next generation of asthma therapeutics with important implications for other eosinophilic diseases such as hypereosinophilic syndrome, Churg-Strauss Syndrome and eosinophilic esophagitis/gastritis.
|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|
|Schwantes, Elizabeth A; Evans, Michael D; Cuskey, Alex et al. (2018) Elevated fractional exhaled nitric oxide and blood eosinophil counts are associated with a 17q21 asthma risk allele in adult subjects. J Asthma Allergy 11:1-9|
|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|
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