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dc.contributor.advisorCorey, David R.en
dc.creatorHolohan, Brody Christopheren
dc.date.accessioned2018-06-04T18:49:28Z
dc.date.available2018-06-04T18:49:28Z
dc.date.created2015-05
dc.date.issued2015-04-07
dc.date.submittedMay 2015
dc.identifier.urihttp://hdl.handle.net/2152.5/5288
dc.description.abstractTelomeres, which are structures that cap the ends of linear chromosomes are maintained by telomerase, a reverse transcriptase. Telomere length limits the self-renewal capacity for telomerase negative cells, and nearly all tumors circumvent this limitation through telomerase expression; as such, telomerase is an attractive target for cancer therapy. In order to identify new targets for anti-telomerase therapy, I demonstrate that a number of candidate genes are required for telomere maintenance in vitro through shRNA-mediated knockdown and telomere length analysis. Further, I show that Perifosine, a drug identified upstream of a number of the candidates can act as a telomerase inhibitor in a majority of cell lines evaluated in vitro as well as induce shortening of the shortest telomeres in tumors from human patients treated with Perifosine in a phase II clinical trial. Additionally, I identify a trans-generational trend in telomere length at birth in human populations that may bias estimates of telomere shortening rate that has public health implications. Lastly, using data from a large twin study, I have identified a network of genes that regulate the rate of telomere shortening in humans that may be used to clarify the association between telomere length, aging and age-related disease.en
dc.format.mimetypeapplication/pdfen
dc.language.isoenen
dc.subjectEnzyme Inhibitorsen
dc.subjectNeoplasmsen
dc.subjectPhosphorylcholineen
dc.subjectTelomeraseen
dc.titleIdentifying, Characterizing and Inhibiting the Telomerase Regulatory Networken
dc.typeThesisen
dc.date.updated2018-06-04T18:41:23Z
dc.type.materialtexten
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.nameDoctor of Philosophyen
thesis.degree.levelDoctoralen
thesis.degree.disciplineCancer Biologyen
dc.contributor.committeeMemberBrekken, Rolf A.en
dc.contributor.committeeMemberCobb, Melanie H.en
dc.contributor.committeeMemberShay, Jerry W.en
dc.contributor.committeeMemberWright, Woodring E.en
dc.identifier.oclc1038532920
dc.creator.orcid0000-0001-6363-7744


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