The role of IRE1 in metaflammation and atherosclerosis

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buir.advisorErbay, Ebru
dc.contributor.authorTufanlı, Özlem
dc.date.accessioned2017-07-07T14:06:22Z
dc.date.available2017-07-07T14:06:22Z
dc.date.copyright2017-05
dc.date.issued2017-05
dc.date.submitted2017-06-30
dc.descriptionCataloged from PDF version of article.en_US
dc.descriptionThesis (Ph.D.): Bilkent University, Department of Molecular Biology and Genetics, İhsan Doğramacı Bilkent University, 2017.en_US
dc.descriptionIncludes bibliographical references (leaves 134-158).en_US
dc.description.abstractChronic metabolic overloading of anabolic and catabolic organelles such as the endoplasmic reticulum (ER) and mitochondria is a major cause of inflammation in obesity. ER serves as a critical metabolic center for protein, lipid and calcium metabolism. ER’s vital functions are maintained by a conserved, adaptive stress response known as the Unfolded Protein Response (UPR), which strives to re-establish homeostasis. Irremediable ER stress, however, can push the UPR to initiate proinflammatory and pro-apoptotic signaling. UPR activation is seen in all stages of atherosclerotic plaque formation and ER stress is causally associated with atherosclerosis. A profound interest in therapeutically limiting ER stress in a variety of human diseases has driven the discovery of small molecules that can modulate specific UPR signaling arms. These UPR modulators can also become tools to understand the distinct contribution of UPR branches to atherogenesis. In my studies I utilized a specific inhibitor for Inositol-requiring enzyme-1 (IRE1), a dual kinase and endoribonuclease (RNase) in the UPR, to define IRE1’s RNA substrates in macrophages. Using RNA sequencing, I discovered that IRE1’s RNase activity regulates many pro-atherogenic and pro-inflammatory genes in macrophages. The outcome of my studies provides compelling evidence that IRE1, through its target XBP1, regulates the inflammatory response to lipid excess. The data shows that specific inhibitors of IRE1’s RNase activity can uncouple lipid-induced ER stress from immune response in both mouse and human macrophages by blocking mitochondrial reactive oxygen species production and NLRP3 inflammasome activation. Furthermore, administrating two small molecule inhibitors of IRE1’s RNase activity to hypercholestrolemic ApoE deficient (ApoE-/-) mice led to profound suppression of pro-atherogenic cytokine levels in the circulation and blunted T helper-1 type immune response, thus alleviating atherosclerosis. These results demonstrate that therapeutic fine-tuning of IRE1’s RNase activity with small molecule inhibitors could be developed further for atherosclerosis.en_US
dc.description.provenanceSubmitted by Betül Özen (ozen@bilkent.edu.tr) on 2017-07-07T14:06:22Z No. of bitstreams: 1 ÖZLEM_TUFANLI_TEZ.pdf: 8438069 bytes, checksum: 83a6aca06ad7f9ae7d38bf0502b6d15b (MD5)en
dc.description.provenanceMade available in DSpace on 2017-07-07T14:06:22Z (GMT). No. of bitstreams: 1 ÖZLEM_TUFANLI_TEZ.pdf: 8438069 bytes, checksum: 83a6aca06ad7f9ae7d38bf0502b6d15b (MD5) Previous issue date: 2017-06en
dc.description.statementofresponsibilityby Özlem Tufanlı.en_US
dc.embargo.release2020-06-30
dc.format.extentxxi, 183 pages : illustrations (some color), charts ; 29 cmen_US
dc.identifier.itemidB155874
dc.identifier.urihttp://hdl.handle.net/11693/33372
dc.language.isoEnglishen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectMetaflammationen_US
dc.subjectUnfolded protein responseen_US
dc.subjectMitochondrial oxidative stressen_US
dc.subjectReactive oxygen speciesen_US
dc.subjectEndoplasmic reticulum stressen_US
dc.subjectInflammasomeen_US
dc.subjectAtherosclerosisen_US
dc.titleThe role of IRE1 in metaflammation and atherosclerosisen_US
dc.title.alternativeIRE1’in metaflamasyon ve aterosklerozdaki rolüen_US
dc.typeThesisen_US
thesis.degree.disciplineMolecular Biology and Genetics
thesis.degree.grantorBilkent University
thesis.degree.levelDoctoral
thesis.degree.namePh.D. (Doctor of Philosophy)

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