Identifying, Characterizing and Inhibiting the Telomerase Regulatory Network
Holohan, Brody Christopher
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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.