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dc.contributor.advisorMichelle Kelliher
dc.contributor.authorZelic, Matija
dc.date2022-08-11T08:08:46.000
dc.date.accessioned2022-08-23T16:07:53Z
dc.date.available2022-08-23T16:07:53Z
dc.date.issued2018-01-18
dc.date.submitted2018-01-31
dc.identifier.doi10.13028/M2GQ3V
dc.identifier.urihttp://hdl.handle.net/20.500.14038/32337
dc.description.abstractNecroptosis, a type of regulated necrotic cell death, involves cell membrane permeabilization and has been implicated in various acute and chronic pro-inflammatory diseases, including ischemia-reperfusion injury and neurodegenerative diseases. By using in vitro reconstitution studies and a chemical inhibitor, the kinase activity of the serine/threonine kinase RIPK1 had been shown to regulate necroptotic signaling downstream of TNF and Toll-like receptors (TLRs). To investigate the contribution of RIPK1 kinase activity to inflammation and necroptosis in vivo, we generated kinase inactive RIPK1 knock-in mice. Utilizing fibroblasts and macrophages from these mice, we demonstrate that RIPK1 kinase activity is required for necroptotic complex formation and death induction downstream of TNFR1 and TLRs 3 and 4. We show that RIPK1 kinase inactive mice are resistant to TNF-induced shock and exhibit impaired upregulation of TNF-induced cytokines and chemokines in vitro and in vivo. By using bone marrow reconstitution experiments, we demonstrate that RIPK1 kinase activity in a non-hematopoietic lineage drives TNF-induced lethality. We establish that RIPK1 kinase activity is required for TNF-induced increases in intestinal and vascular permeability and clotting, and implicate endothelial cell necroptosis as an underlying factor contributing to TNF/zVAD-induced shock. Thus, work in this thesis reveals that RIPK1 kinase inhibitors may have promise in treating shock and sepsis.
dc.language.isoen_US
dc.rightsLicensed under a Creative Commons license
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectInflammation
dc.subjectcell death
dc.subjectRIPK1
dc.subjectTNF
dc.subjectshock
dc.subjectsepsis
dc.subjectAnimal Experimentation and Research
dc.subjectOther Immunology and Infectious Disease
dc.titleThe Role of RIPK1 Kinase Activity in Regulating Inflammation and Necroptotic Death
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1958&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/952
dc.legacy.embargo2019-01-31T00:00:00-08:00
dc.identifier.contextkey11459699
refterms.dateFOA2022-08-24T04:31:28Z
html.description.abstract<p>Necroptosis, a type of regulated necrotic cell death, involves cell membrane permeabilization and has been implicated in various acute and chronic pro-inflammatory diseases, including ischemia-reperfusion injury and neurodegenerative diseases. By using in vitro reconstitution studies and a chemical inhibitor, the kinase activity of the serine/threonine kinase RIPK1 had been shown to regulate necroptotic signaling downstream of TNF and Toll-like receptors (TLRs). To investigate the contribution of RIPK1 kinase activity to inflammation and necroptosis <em>in vivo</em>, we generated kinase inactive RIPK1 knock-in mice. Utilizing fibroblasts and macrophages from these mice, we demonstrate that RIPK1 kinase activity is required for necroptotic complex formation and death induction downstream of TNFR1 and TLRs 3 and 4. We show that RIPK1 kinase inactive mice are resistant to TNF-induced shock and exhibit impaired upregulation of TNF-induced cytokines and chemokines <em>in vitro</em> and <em>in vivo</em>. By using bone marrow reconstitution experiments, we demonstrate that RIPK1 kinase activity in a non-hematopoietic lineage drives TNF-induced lethality. We establish that RIPK1 kinase activity is required for TNF-induced increases in intestinal and vascular permeability and clotting, and implicate endothelial cell necroptosis as an underlying factor contributing to TNF/zVAD-induced shock. Thus, work in this thesis reveals that RIPK1 kinase inhibitors may have promise in treating shock and sepsis.</p>
dc.identifier.submissionpathgsbs_diss/952
dc.contributor.departmentMolecular, Cell and Cancer Biology
dc.description.thesisprogramCancer Biology
dc.identifier.orcid0000-0003-4901-5580


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