Identifying, Characterizing and Inhibiting the Telomerase Regulatory Network
dc.contributor.advisor | Corey, David R. | en |
dc.contributor.committeeMember | Brekken, Rolf A. | en |
dc.contributor.committeeMember | Cobb, Melanie H. | en |
dc.contributor.committeeMember | Shay, Jerry W. | en |
dc.contributor.committeeMember | Wright, Woodring E. | en |
dc.creator | Holohan, Brody Christopher | en |
dc.creator.orcid | 0000-0001-6363-7744 | |
dc.date.accessioned | 2018-06-04T18:49:28Z | |
dc.date.available | 2018-06-04T18:49:28Z | |
dc.date.created | 2015-05 | |
dc.date.issued | 2015-04-07 | |
dc.date.submitted | May 2015 | |
dc.date.updated | 2018-06-04T18:41:23Z | |
dc.description.abstract | Telomeres, 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.mimetype | application/pdf | en |
dc.identifier.oclc | 1038532920 | |
dc.identifier.uri | https://hdl.handle.net/2152.5/5288 | |
dc.language.iso | en | en |
dc.subject | Enzyme Inhibitors | en |
dc.subject | Neoplasms | en |
dc.subject | Phosphorylcholine | en |
dc.subject | Telomerase | en |
dc.title | Identifying, Characterizing and Inhibiting the Telomerase Regulatory Network | en |
dc.type | Thesis | en |
dc.type.material | text | en |
thesis.degree.department | Graduate School of Biomedical Sciences | en |
thesis.degree.discipline | Cancer Biology | en |
thesis.degree.grantor | UT Southwestern Medical Center | en |
thesis.degree.level | Doctoral | en |
thesis.degree.name | Doctor of Philosophy | en |