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dc.contributor.advisorMukherji, Mriduleng
dc.contributor.authorVavilala, Divya Tejaeng
dc.date.issued2015-06-02eng
dc.date.submitted2014 Falleng
dc.descriptionTitle from PDF of title page, viewed in June 30, 2015eng
dc.descriptionDissertation advisor: Mridul Mukherjieng
dc.descriptionVitaeng
dc.descriptionIncludes bibliographic references (pages 107-127)eng
dc.descriptionThesis (Ph.D.)--School of Pharmacy and School of Biological Sciences. University of Missouri--Kansas City, 2014eng
dc.description.abstractHypoxia-inducible-factor (HIF)-mediated expression of pro-angiogenic genes under hypoxia is the fundamental cause of pathological neovascularization in ocular diseases and cancers. Thus, the inhibitors of the HIF pathway or key regulators such as histone demethylases (KDMs), that amplify HIF signaling, can have profound therapeutic value for these diseases. This dissertation reports findings about phytochemical molecules - honokiol and berberine and shows them to be potent inhibitors of the HIF pathway as well as hypoxiainduced expression of KDMs in a number of cancer and retinal pigment epithelial cell lines. The results provide an evidence-based scientific explanation for therapeutic benefits observed with honokiol and berberine. On comparing the anti-HIF effect of both these compounds honokiol was found to possess a better efficacy that exhibited it's effect on the HIF pathway by inhibiting HIF binding to the HRE. Further in this study honokiol was compared with two other recently identified HIF inhibitors from natural sources - digoxin and doxorubicin. The results show that honokiol has a better safety to efficacy profile as a HIF inhibitor than digoxin and doxorubicin. Therefore honokiol was chosen as candidate molecule for further clinical evaluation for the treatment of pathological ocular neovascularization. Honokiol inhibited hypoxic - mediated secretion of VEGF by retinal pigment epithelial cells. Hence honokiol’s anti-angiogenic activity was evaluated using various in vitro angiogenesis assays that mimic ocular neovascularization. A robust inhibition of human retinal micro vascular endothelial cell (hRMVEC) activation and proliferation was observed with honokiol treatment. Also, hRMVEC cells lost their ability to migrate and form wellnetworked tubes essential for pathological ocular neovascularization. Further, it is shown for the first time that daily intraperitoneally injection of honokiol starting at postnatal day (P) 12 in an oxygen-induced retinopathy (OIR) mouse model significantly reduced retinal neovascularization at P17. Administration of honokiol also prevents the oxygen-induced central retinal vaso-obliteration a characteristic feature of the OIR model. Honokiol also enhanced physiological revascularization of the retinal vascular plexuses. Since honokiol suppresses multiple pathways activated by HIF, in addition to the VEGF signaling, it may provide advantages over current treatments utilizing specific VEGF antagonists for ocular neovascular diseases and cancers.eng
dc.description.tableofcontentsIntroduction and literature review -- In vitro screening for HIF pathway inhibitors -- Evaluating Honokiol's mechanism of HIF pathway inhibition -- Evaluating Honokiol's anti-angiogenic activity -- Appendixeng
dc.format.extentxxiii, 128 pageseng
dc.identifier.urihttps://hdl.handle.net/10355/45811eng
dc.subject.lcshEye -- Diseases -- Treatment.eng
dc.subject.meshEye Diseases -- therapyeng
dc.subject.otherDissertation -- University of Missouri--Kansas City -- Pharmacyeng
dc.subject.otherDissertation -- University of Missouri--Kansas City -- Biologyeng
dc.titleEvaluation Of HIF Inhibitors For The Treatment of Ocular Neovascular Diseaseseng
dc.typeThesiseng
thesis.degree.disciplinePharmaceutical Sciences (UMKC)eng
thesis.degree.disciplineMolecular Biology and Biochemistry (UMKC)
thesis.degree.grantorUniversity of Missouri--Kansas Cityeng
thesis.degree.levelDoctoraleng
thesis.degree.namePh.D.eng


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