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dc.contributor.authorPang, Zheng
dc.date.accessioned2019-10-29T14:09:49Z
dc.date.available2019-10-29T14:09:49Z
dc.identifier.urihttp://hdl.handle.net/10222/76553
dc.description.abstractPseudomonas aeruginosa is an opportunistic pathogen that is a common cause of nosocomial infections in immunocompromised individuals. The healthy individuals effectively clear P. aeruginosa infections through tightly controlled inflammatory responses. Dysregulated inflammation increases host susceptibility to P. aeruginosa infections and causes severe lung damage. The molecular mechanisms governing the inflammatory responses to P. aeruginosa infections remain incompletely defined. Herein, I identified a novel role of regulator of calcineurin-1 (RCAN1) in P. aeruginosa lipopolysaccharide (LPS)-activated TLR4 signaling, and a detrimental role of early growth response 1 (Egr-1) in host defense against P. aeruginosa lung infection. RCAN1, a small evolutionarily conserved protein that inhibits calcineurin phosphatase activity, functions as a negative regulator of inflammation. I found that RCAN1 downregulates myeloid differentiation primary response 88 (MyD88)-NF-κB pathway through inhibition of IκBα phosphorylation, and promotes activation of TIR-domain-containing adapter-inducing interferon-β (TRIF)-interferon-stimulated response element (ISRE) pathway through regulation of IRF7 activation and expression. Egr-1 is a zinc-finger transcription factor that controls inflammatory responses. I demonstrated that Egr-1 promotes inflammation associated with increased mortality, and negatively regulates nitric oxide production for bacterial clearance during P. aeruginosa lung infection. Together, these findings improve our understanding of regulatory mechanisms involved in host defense against P. aeruginosa infections in innate immunity, and suggest that RCAN1 and Egr-1 could be potential therapeutic targets to enhance bacterial clearance or reduce the risk of systemic inflammation.en_US
dc.language.isoenen_US
dc.subjectPseudomonas aeruginosaen_US
dc.subjectlung infectionen_US
dc.subjectRCAN1en_US
dc.subjectEgr-1en_US
dc.titleRegulation of inflammation during Pseudomonas aeruginosa lung infectionen_US
dc.date.defence2019-10-21
dc.contributor.departmentDepartment of Pathologyen_US
dc.contributor.degreeDoctor of Philosophyen_US
dc.contributor.external-examinerSimon Rousseauen_US
dc.contributor.graduate-coordinatorKaren Bedarden_US
dc.contributor.thesis-readerCraig McCormicken_US
dc.contributor.thesis-readerDavid Hoskinen_US
dc.contributor.thesis-readerBeata Derfalvien_US
dc.contributor.thesis-supervisorZhenyu Chengen_US
dc.contributor.ethics-approvalReceiveden_US
dc.contributor.manuscriptsYesen_US
dc.contributor.copyright-releaseNoen_US
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