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.
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