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dc.contributor.advisorLubahn, Dennis B.eng
dc.contributor.authorStarkey, Nicholas J. E.eng
dc.date.issued2018eng
dc.date.submitted2018 Springeng
dc.description.abstract[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The estrogen receptors alpha (ER[alpha]) and beta (ER[beta]) are important regulators of development and growth in many major organ systems. In the tissues they are co-expressed in, ER[alpha] is often a stimulator, and ER[beta] an inhibitor, of proliferation and inflammation. Although ER[beta] selective agonists effectively treat multiple pre-clinical disease models, none have been effective in humans. In this dissertation, we studied exogenous (botanicals/fungals) and endogenous (oxysterols) molecules that we hypothesized could effectively modulate the human ERs in a subtype selective manner. Unfortunately, the exogenous botanicals/fungals tested did not activate ER[beta] or inhibit ER[alpha] with >3-fold selectivity. However, the endogenous oxysterol, 27-hydroxycholesterol (27-OHC) bound selectively (>100-fold) to ER[beta] over ER[alpha] and acted as a selective antagonist (>10-fold). We found that 27-OHC is a negative allosteric modifier of 17{beta]-estradiol binding to ER[beta], with a physiologically relevant Ki of 50nM and cooperativity factor ([alpha]) of 0.036. We also proposed a 3D in silico model of combined docking attempts with 27-OHC in the orthosteric site and E2 in an alternate site in ER[beta]. These findings may help explain the lack of effectiveness of ER[beta] selective agonists in clinical trials and lead to better ER[beta] based treatments for human diseases in the future.eng
dc.format.extentx, 109 pages : illustrationeng
dc.identifier.urihttps://hdl.handle.net/10355/68942
dc.identifier.urihttps://doi.org/10.32469/10355/68942eng
dc.languageEnglisheng
dc.publisherUniversity of Missouri--Columbiaeng
dc.relation.ispartofcommunityUniversity of Missouri--Columbia. Graduate School. Theses and Dissertationseng
dc.rightsAccess to files is limited to the University of Missouri--Columbia.eng
dc.titleSelective modulation of estrogen receptors : 27-hydroxycholesterol is a negative allosteric modulator of er-beta activity and estradiol bindingeng
dc.typeThesiseng
thesis.degree.disciplineBiochemistry (MU)eng
thesis.degree.grantorUniversity of Missouri--Columbiaeng
thesis.degree.levelDoctoraleng
thesis.degree.namePh. D.eng


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