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dc.contributor.authorSingh, Neerajen_US
dc.date.accessioned2017-04-06T15:43:09Z
dc.date.available2017-04-06T15:43:09Z
dc.date.issued2010-07-14en_US
dc.identifier.otheretd-07262010-131201en_US
dc.identifier.urihttp://hdl.handle.net/10919/77145
dc.description.abstractOxidative stress plays a vital role in the pathogenesis of many chronic and acute inflammatory diseases. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are two key mediators that are known to induce cellular and tissue oxidative stress. The generation of ROS and RNS is mediated by innate immune signaling processes. Lipopolysaccharide (LPS), a major inflammatory signal, is known to be a potent inducer of ROS/RNS. Thus, strategies that may block LPS-mediated generation of free radicals may hold promise in treating various inflammatory disease processes. However, the molecular mechanisms underlying LPS-mediated ROS/RNS production are not fully defined. Interleukin-1 Receptor associated kinase (IRAK-1), an intracellular kinase downstream of Toll-like Receptor 4 (TLR4) has been shown to contribute to the inflammatory cascade associated with LPS-TLR4 signaling pathway. However, its role in ROS production has not been defined. Therefore, we tested the hypothesis that IRAK-1 plays an important role in regulating ROS/RNS production. Both in vitro and in vivo studies were conducted to investigate the role of IRAK-1 in modulating free radicals as well as oxidative stress. In vitro studies demonstrate that IRAK-1 is a critical molecule involved in the induction of ROS/RNS. IRAK-1 deletion ablated free radical production following LPS challenge in a variety of cell types including macrophages, fibroblasts and microglia. Mechanistically, we observed that IRAK-1 is required for optimal expression and activity of NADPH oxidase subunits and iNOS. IRAK-1 deletion reduced LPS-triggered p47phox membrane translocation, suppressed NOX-1 expression and protein levels as well as hampered Rac1 activation. On the other hand, IRAK-1 deletion sustained antioxidative enzyme activity and levels in IRAK-1-/- macrophages and fibroblasts. In terms of the in vivo physiological consequences, IRAK-1-/- mice exhibited attenuated lipid peroxidation in vital organs, attenuated histopathological lesions in liver and kidney, and reduced endotoxemia-associated mortality. Taken together, IRAK-1 may, at least in part, serve as an important therapeutic target in the treatment of various inflammatory disease processes.
dc.language.isoen_USen_US
dc.publisherVirginia Techen_US
dc.rightsI hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Virginia Tech or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.en_US
dc.subjectAll-trans Retinoic Aciden_US
dc.subjectFree radicalsen_US
dc.subjectMacrophagesen_US
dc.subjectIRAK-1en_US
dc.subjectLipopolysaccharideen_US
dc.subjectSepsisen_US
dc.subjectNADPH oxidaseen_US
dc.subjectiNOSen_US
dc.titleThe Role of IRAK-1 in the Regulation of Free Radicals and Oxidative Stress during Endotoxemiaen_US
dc.typeDissertationen_US
dc.contributor.departmentVeterinary Medical Sciencesen_US
dc.description.degreePh. D.en_US
thesis.degree.namePh. D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen_US
thesis.degree.disciplineVeterinary Medical Sciencesen_US
dc.contributor.committeechairLi, Liwuen_US
dc.contributor.committeememberLeRoith, Tanyaen_US
dc.contributor.committeememberMisra, Hara P.en_US
dc.contributor.committeememberMahaney, James E.en_US
dc.contributor.committeememberYuan, Lijuanen_US
dc.type.dcmitypeTexten_US
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-07262010-131201/en_US
dc.date.sdate2010-07-26en_US
dc.date.rdate2016-10-18
dc.date.adate2010-07-30en_US


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