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dc.contributor.authorBaker, Bianca Nicoleen_US
dc.date.accessioned2015-10-07T06:00:32Z
dc.date.available2015-10-07T06:00:32Z
dc.date.issued2014-04-14en_US
dc.identifier.othervt_gsexam:2639en_US
dc.identifier.urihttp://hdl.handle.net/10919/56732
dc.description.abstractThe gram-negative endotoxin, lipopolysaccharide (LPS), has been extensively researched in high doses (10-200ng/ml) and is well-documented in the literature for its ability to result in devastating effects such as multi-organ failure, sepsis, and septic shock. In high doses, LPS signals through Toll-like-receptor 4 (TLR4) and triggers a cascade of events culminating in the release of pro- and anti-inflammatory cytokines and the activation of NF-�[BULLET]B. In contrast, super-low doses of LPS (1-100pg/ml) are able to trigger the persistent release of pro-inflammatory mediators while evading the compensatory activation of NF-�[BULLET]B. This mild yet persistent induction of inflammation may lie at the heart of numerous inflammatory diseases and disorders and warrants studies such as this to elucidate the novel mechanisms. In this study, we explored the novel mechanisms utilized by super-low dose LPS in cellular stress and low-grade inflammation. In the first study, the molecular mechanisms governing the role of super-low dose LPS on cellular stress and necroptosis were examined. We show that in the presence of super-low dose LPS (50pg/ml), the key regulators of mitochondrial fission and fusion, Drp1 and Mfn1 respectively, are inversely regulated. An increase in mitochondrial fragmentation and cell death which was not dependent on caspase activation was observed. In addition, super-low dose LPS was able to activate RIP3, a kinase responsible for inducing the inflammatory cell death, necroptosis. These mechanisms were regulated in an Interleukin-1 receptor-associated kinase 1 (IRAK-1) dependent manner. In the second study, the molecular mechanisms governing the role of super-low dose LPS on cellular stress and endosome/lysosome fusion were examined. In the presence of low-dose LPS (50pg/ml), endosomal-lysosomal fusion is inhibited and a loss of endosomal acidification required for the successful clearance of cellular debris and resolution of inflammation was observed. Additionally, super-low dose LPS induced the accumulation of p62 indicative of the suppression of autophagy. Tollip and Interleukin-1 receptor-associated kinase 3 (IRAK-M) appear to be critical regulators in this process. Collectively, these studies show that low-dose endotoxemia is capable of causing persistent cellular stress, not observed in the presence of high-dose LPS (10-200ng/ml), and that it promotes necroptotic cell death while suppressing mechanisms necessary for the resolution of inflammation such as endosome-lysosome fusion. This research reveals novel mechanisms utilized by low-dose endotoxemia which could aid future efforts to develop prevention and treatment for various debilitating inflammatory diseases.en_US
dc.format.mediumETDen_US
dc.publisherVirginia Techen_US
dc.rightsThis Item is protected by copyright and/or related rights. Some uses of this Item may be deemed fair and permitted by law even without permission from the rights holder(s), or the rights holder(s) may have licensed the work for use under certain conditions. For other uses you need to obtain permission from the rights holder(s).en_US
dc.subjectLipopolysaccharideen_US
dc.subjectinflammationen_US
dc.subjectcell deathen_US
dc.subjectmitochondrial dynamicsen_US
dc.subjectendosome-lysosome fusionen_US
dc.titleMolecular and Cellular Mechanisms Responsible for Low-grade Stress and Inflammation Triggered By Super-low Dose Endotoxinen_US
dc.typeDissertationen_US
dc.contributor.departmentBiological Sciencesen_US
dc.description.degreePHDen_US
thesis.degree.namePHDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen_US
thesis.degree.disciplineBiological Sciencesen_US
dc.contributor.committeechairLi, Liwuen_US
dc.contributor.committeememberSubbiah, Elankumaranen_US
dc.contributor.committeememberHulver, Matthew Wadeen_US
dc.contributor.committeememberSchubot, Florian Daviden_US


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