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Principal Investigator: Fu, Jian
Institute Receiving Award University Of Kentucky
Location Lexington, KY
Grant Number R21ES028752
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Aug 2018 to 31 Jul 2021
DESCRIPTION (provided by applicant): Project Summary Epithelial barrier dysfunction contributes to the pathogenesis of infection, inflammation and injury. E-Cadherin, a component of epithelial adherens junctions, plays an essential role in maintaining epithelial barrier function. Cigarette smoke exposure has been reported to downregulate E-Cadherin expression in epithelial cells. However, molecular mechanisms of cigarette smoke-induced suppression of E-Cadherin expression and epithelial barrier dysfunction remain largely unknown. In this project, we will investigate the role of a histone methyltransferase, euchromatic histone-lysine N-methyltransferase 2 (EHMT2 or G9a), in cigarette smoke-induced E-cadherin downregulation and epithelial barrier dysfunction. EHMT2 specifically methylates Histone H3 at lysine 9 (H3K9). Methylation of H3K9 by EHMT2 regulates gene expression by silencing euchromatin. Our preliminary data demonstrate that EHMT2 expression is robustly up-regulated in cigarette smoke-exposed normal human bronchial epithelial cells (NHBEs). The up-regulation of EHMT2 is associated with high levels of H3K9 methylation and E-Cadherin downregulation. EHMT2 knockdown or selective inhibition was able to restore E-Cadherin expression in cigarette smoke-exposed NHBEs. Furthermore, in a mouse model of cigarette smoke exposure, lung EHMT2 expression and H3K9 methylation were increased, which was associated with E-cadherin downregulation and epithelial barrier disruption in lung tissues. In the proposed studies, we will test we will test the hypothesis that EHMT2 up-regulation by chronic tobacco smoke exposure leads to epigenetic suppression of E-Cadherin expression and epithelial barrier dysfunction. Our specific aims are: (1) To determine the role of EHMT2 in epigenetic suppression of E-Cadherin expression and epithelial barrier dysfunction in tobacco smoke-exposed human bronchial epithelial cells. (2) To explore therapeutic mechanisms of EHMT2 inhibition against tobacco smoke-induced epithelial barrier dysfunction in vivo. Our studies could reveal new therapeutic targets to treat environmental tobacco smoke-induced epithelial cell dysfunction.
Science Code(s)/Area of Science(s) Primary: 69 - Respiratory
Publications No publications associated with this grant
Program Officer Frederick Tyson
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