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    Targeting the Activator Protein-1 Complex to Inhibit Airway Smooth Muscle Cell Hyperproliferation in Asthma

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    Author
    Defnet, Amy Elizabeth
    Advisor
    Shapiro, Paul, Ph.D.
    Kane, Maureen A.
    Date
    2021
    Type
    dissertation
    
    Metadata
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    Abstract
    Hyperproliferation of airway smooth muscle (ASM) cells leads to increased ASM mass causing airway obstruction in inflammatory diseases such as asthma. Currently, there are no effective therapies to modulate ASM cell proliferation that contributes to debilitating bronchoconstriction in severe asthmatics. Previous studies suggest that activator protein-1 (AP-1) transcription factor expression is upregulated in airway cells in asthma and inhibition of AP-1 could mitigate the hyperproliferation of ASM cells. AP-1 activity has been shown to be enhanced by upstream extracellular signal-regulated kinase (ERK1/2) signaling or antagonized by retinoic acid receptor (RAR)-mediated signaling. The overall goal of the current study was to evaluate the therapeutic potential of a combination therapy of an ERK1/2 inhibitor and RAR agonist to modulate AP-1 complex formation and activation. Aim 1 studies tested the hypothesis that a novel function-selective ERK1/2 inhibitor, referred to as SF-3-030, would mitigate off-target toxicity while regulating platelet-derived growth factor (PDGF) induced AP-1 activity and ASM cell proliferation. In Aim 2 studies we evaluated the role of retinoids in controlling AP-1 complex formation and identified a RARγ isoform-specific agonist, CD1530, as a potential therapeutic option for inhibition of AP-1 activity and ASM cell hyperproliferation. Aim 3 studies determined whether a polypharmacological approach of combining ERK1/2 inhibition and RAR agonism to target two different aspects of the AP-1 complex activation and formation would have an additive effect in preventing ASM hyperproliferation. Overall, these studies help further our understanding of how AP-1 signaling causes the hyperproliferation of ASM cells while elucidating possible therapeutic treatment options through ERK1/2 inhibition and RAR agonism.
    Description
    Pharmaceutical Sciences
    University of Maryland, Baltimore
    Ph.D.
    Keyword
    Activator Protein-1
    airway smooth muscle
    retinoic acid
    Airway Remodeling
    Asthma
    Protein Kinases
    Transcription Factor AP-1
    Tretinoin
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/15769
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    Theses and Dissertations School of Pharmacy
    Theses and Dissertations All Schools

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