Excess airway fibrosis is among the most significant sequelae of long-term asthma. Airways in patients with chronic asthma are often remodeled, becoming thickened and less elastic, resulting in reduced airflow despite increased respiratory effort. The remodeling airway contains cytokine producing immune cells, particularly eosinophils (EOS) and activated fibroblasts (Fb) that generate pathologic amounts of profibrotic mediators and extracellular matrix (ECM), Fb ECM production is driven by excess levels of profibrotic cytokines, especially TGF-(31 that are principally elaborated by activated EOS, Despite its importance in key physiologic processes such as wound healing and tissue homeostasis, the signaling cascades elicited in Fb or EOS by TGF-(31 remain incompletely understood, and have yet to be effectively targeted for therapeutics to block or attenuate airway remodeling. We hypothesize that Pin1 modulates TGF-pi signaling by interacting with and isomerizing proximal Smads (3 and 6) as well as Pl-S-Ky and Akt, We further hypothesize that ablation of Pin1 in pulmonary Fb or peripheral blood EOS will attenuate airway remodeling in allergen challenged rodents. In order to test these hypotheses, we propose to:
Aim 1 : Identify how Pint influences Smad6 function. We have shown that Pin1 binds to and controls the intracellular location of Smad6, We will first identify and then mutate Smad6 sites that mediate an interaction with Pin1. Mutant Smad6 proteins will be expressed in Fb and EOS and the functional consequences on Smad6, Smad3, Pin1 function and location and TGF-(31 induced gene expression will be determined.
Aim 2 : Determine how Pin1 and PI-3-Ky affects Smad3 function and signaling. TGF-pi induces Pin1 to bind to both PI-3-KY and Akt, Furthermore, inhibitors of PI-3-K or Pin1 prevented Smad3 translocation and ECM production, suggesting a common pathway. Thus, we will define how Akt function and interaction with Smad3 are controlled by Pin1 and PI-3-K in both murine and human Fb and human EOS.
Aim 3 : To test the effects of tissue and cell selective Pin1 KO on airway remodeling, EOS inflammation, cytokine expression, Fb proliferation and ECM production following acute and chronic allergen challenge. In aggregate, these studies will characterize how Pin1 regulates TGF-pi signaling and ECM production.
The studies will enhance our understanding of how the lung responds to damage initiated by inhalation of allergen. With this knowledge may come new approaches to slow or stop these destructive processes before they become debilitating.
|Schwantes, E A; Manthei, D M; Denlinger, L C et al. (2014) Interferon gene expression in sputum cells correlates with the Asthma Index Score during virus-induced exacerbations. Clin Exp Allergy 44:813-21|
|Esnault, Stephane; Kelly, Elizabeth A; Johansson, Mats W et al. (2014) Semaphorin 7A is expressed on airway eosinophils and upregulated by IL-5 family cytokines. Clin Immunol 150:90-100|
|Wickert, Lisa E; Karta, Maya R; Audhya, Anjon et al. (2014) Simvastatin attenuates rhinovirus-induced interferon and CXCL10 secretion from monocytic cells in vitro. J Leukoc Biol 95:951-9|
|Karta, Maya R; Gavala, Monica L; Curran, Colleen S et al. (2014) LPS modulates rhinovirus-induced chemokine secretion in monocytes and macrophages. Am J Respir Cell Mol Biol 51:125-34|
|Han, Shih-Tsung; Mosher, Deane F (2014) IL-5 induces suspended eosinophils to undergo unique global reorganization associated with priming. Am J Respir Cell Mol Biol 50:654-64|
|Mathur, Sameer K; Viswanathan, Ravi K (2014) Relevance of allergy in adult asthma. Curr Allergy Asthma Rep 14:437|
|Burnham, Mandy E; Esnault, Stephane; Roti Roti, Elon C et al. (2014) Cholesterol selectively regulates IL-5 induced mitogen activated protein kinase signaling in human eosinophils. PLoS One 9:e103122|
|Karta, Maya R; Wickert, Lisa E; Curran, Colleen S et al. (2014) Allergen challenge in vivo alters rhinovirus-induced chemokine secretion from human airway macrophages. J Allergy Clin Immunol 133:1227-30|
|Johansson, M W (2014) Activation states of blood eosinophils in asthma. Clin Exp Allergy 44:482-98|
|Oh, Jiyoung; Malter, James S (2013) Pin1-FADD interactions regulate Fas-mediated apoptosis in activated eosinophils. J Immunol 190:4937-45|
Showing the most recent 10 out of 43 publications