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dc.contributor.authorWong, Nathan Kum Pang
dc.date.accessioned2020-08-21
dc.date.available2020-08-21
dc.date.issued2020en_AU
dc.identifier.urihttps://hdl.handle.net/2123/23144
dc.description.abstractAngiogenesis, the formation of new blood vessels from pre-existing vessels, is critical in the pathophysiology of chronic conditions, such as atherosclerotic vascular diseases. While angiogenesis is a key physiological response to ischaemia and wound healing, it is pathological when excessive and driven by inflammation. No current therapies adequately promote hypoxia-driven angiogenesis while inhibiting inflammation-induced angiogenesis. Our group found that high-density lipoproteins (HDL) modulates vessel growth in a contextual manner via classical signalling pathways. Whether novel mediators are involved that would be more amenable as therapeutic targets remains unknown. CREBRF and TRIM2 are two genes with no known roles in vascular biology, identified from a microarray to be upregulated by reconstituted (r)HDL in human endothelial cells (ECs). This thesis hypothesised a novel angiogenic role for these genes and aimed to assess their functional importance via in vitro and in vivo models of hypoxia- and inflammation-driven angiogenesis. CREBRF and TRIM2 were confirmed to be transcriptionally upregulated by rHDL, mainly via its phospholipid component. Lentiviral shRNA knockdown of CREBRF and TRIM2 impaired EC migration, proliferation and tubule-forming capacity in response to hypoxic or inflammatory stimulation in vitro. TRIM2 was also found to mediate the pro-angiogenic actions of rHDL in hypoxia. Mechanistically, TRIM2 knockdown attenuated the induction of key angiogenic mediators in inflammation, including nuclear HIF-1α, NF-κB p65, VEGFA and downstream effectors VEGFR2, p38 MAPK and eNOS. In Trim2–/– mice, the physiological angiogenic response to hindlimb ischaemia was not different to wild-type, however the activation of inflammatory responses to periarterial cuff injury was inhibited. In conclusion, TRIM2 may be a novel regulator of inflammation-induced angiogenesis; and could prove useful as a therapeutic target for diseases driven by pathological vessel growth.en_AU
dc.language.isoenen_AU
dc.publisherUniversity of Sydneyen_AU
dc.subjectangiogenesisen_AU
dc.subjectTRIM2en_AU
dc.subjectCREBRFen_AU
dc.subjecthypoxiaen_AU
dc.subjectinflammationen_AU
dc.subjecthigh-density lipoproteinen_AU
dc.titleExploring the Role of Novel Targets CREBRF and TRIM2 in the Regulation of Angiogenesisen_AU
dc.typeThesis
dc.type.thesisDoctor of Philosophyen_AU
dc.rights.otherThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en_AU
usyd.facultySeS faculties schools::Faculty of Medicine and Healthen_AU
usyd.departmentCentral Clinical Schoolen_AU
usyd.departmentHeart Research Instituteen_AU
usyd.degreeDoctor of Philosophy Ph.D.en_AU
usyd.awardinginstThe University of Sydneyen_AU
usyd.advisorTan, Joanne


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