The respiratory tract is constantly exposed to microbial pathogens and particles, but is protected by a multitiered host defense system that serves to maintain lung function and sterility. Severe defects in mucociliary clearance, mucus production, and host defense accompany common chronic lung diseases, including cystic fibrosis (CF), chronic obstructive pulmonary disease, and asthma. These disorders are complicated by mucus metaplasia, mucus hyperproduction or inspissation, inflammation, and susceptibility to pulmonary infection. This application seeks to determine the molecular mechanisms underlying deficits in mucociliary clearance associated with pulmonary disease in CF. The work is based on preliminary data demonstrating 1) a novel network of transcription factors that determines both the patterning and differentiation of airway epithelial cells (AECs) lining the developing trachea and bronchi, and the formation of submucosal glands (SMGs) that secrete the majority of fluids, electrolytes, and host defense proteins onto the airway surface and 2) that patterning, growth, diferentiation, and gene expression of AECs and SMGs are influenced by the lack of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). This application will test the hypothesis that PAX9 and an associated transcriptional network play a critical role in the regulation of AEC and SMG morphogenesis and function in the developing and mature airway. This proposal will utilize transgenic mice in which PAX9 and genes associated with PAX9 are conditionally deleted or added to the developing and mature airway epithelium in vivo and in vitro. The molecular and cellular mechanisms by which PAX9 and associated proteins regulate genes and processes critical for AEC and SMG formation and function wil be assessed. The role of the proposed PAX9-dependent regulatory program in the pathogenesis of the pulmonary complications of CF will be determined in CFTR-deficient pigs and mice. This proposal seeks to determine the cellular and molecular basis underlying AEC and SMG morphogenesis and function relevant to the pathogenesis of recurrent infections caused by defects in mucociliary clearance.
Throughout life, the lung is exposed to particles, bacteria, viruses, and other microbial pathogens and toxicants that must be removed from the lung by a mucociliary """"""""escalator."""""""" Common, chronic lung diseases, including asthma, chronic obstructive lung disease, and cystic fibrosis (CF) are complicated by mucus hyperproduction and recurrent lung infections, leading to long-term disability and mortality affecting millions of individuals world- wide. This application will identify the mechanisms regulating submucosal gland differentiation and function leading to abnormal airway mucociliary clearance and infection. The grant will identify the processes controlling gene expression that are associated with abnormal submucosal gland formation and function in CF and that are also relevant to the pathogenesis of chronic lung diseases in general. Understanding the processes controlling airway epithelial and submucosal gland function provides a framework for the development of new therapies for chronic lung diseases.
|Davies, Elizabeth R; Kelly, Joanne F C; Howarth, Peter H et al. (2016) Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life. JCI Insight 1:|
|Whitsett, Jeffrey A; Wert, Susan E; Weaver, Timothy E (2015) Diseases of pulmonary surfactant homeostasis. Annu Rev Pathol 10:371-93|
|Whitsett, Jeffrey A; Weaver, Timothy E (2015) Alveolar development and disease. Am J Respir Cell Mol Biol 53:1-7|
|Whitsett, Jeffrey A (2014) The molecular era of surfactant biology. Neonatology 105:337-43|
|Chen, Gang; Korfhagen, Thomas R; Karp, Christopher L et al. (2014) Foxa3 induces goblet cell metaplasia and inhibits innate antiviral immunity. Am J Respir Crit Care Med 189:301-13|
|Tang, Xiaoju; Liu, Xiaojing J; Tian, Cuijie et al. (2013) Foxa2 regulates leukotrienes to inhibit Th2-mediated pulmonary inflammation. Am J Respir Cell Mol Biol 49:960-70|
|Ren, Xiaomeng; Shah, Tushar A; Ustiyan, Vladimir et al. (2013) FOXM1 promotes allergen-induced goblet cell metaplasia and pulmonary inflammation. Mol Cell Biol 33:371-86|
|Cornett, Bridget; Snowball, John; Varisco, Brian M et al. (2013) Wntless is required for peripheral lung differentiation and pulmonary vascular development. Dev Biol 379:38-52|
|Hao, Huifang; Maeda, Yutaka; Fukazawa, Takuya et al. (2013) Inhibition of the growth factor MDK/midkine by a novel small molecule compound to treat non-small cell lung cancer. PLoS One 8:e71093|
|Korfhagen, Thomas R; Kitzmiller, Joseph; Chen, Gang et al. (2012) SAM-pointed domain ETS factor mediates epithelial cell-intrinsic innate immune signaling during airway mucous metaplasia. Proc Natl Acad Sci U S A 109:16630-5|
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