Primary Appointment

• Telomere dysfunction
• Genomic instability and cancer
• Molecular biology of aging
• Molecular cytogenetics analysis of carcinomas
• Mouse models of aging and cancer

Telomeres are G-rich repeat sequences that cap the ends of most eukaryotic chromosomes and serve to protect natural DNA ends from being recognized as double-stranded breaks. The synthesis and maintenance of telomeric repeats are mediated by telomerase, a specialized ribonucleoprotein complex consisting of both RNA and protein components. In the absence of telomerase, progressive telomere shortening triggers the activation of the p53 and Rb tumor suppressor pathways, which provide signals for replicative senescence. Disruption of p53 and RB can extend the replicative potential, however, continuous cellular proliferation drives further telomere shortening, culminating in telomere erosion and entry into a crisis phase of rampant genomic instability and cell death. Both senescence and crisis are potent tumor suppressor mechanisms. Therefore, human cancer cells must activate telomere maintenance programs in order to proliferate indefinitely. Reactivation of telomerase is observed in the majority of human cancers, and is a critical event that promotes sustained tumor cell proliferation by removing the short telomeric barriers necessary for tumor progression.

My research interests lie in understanding the role and regulation of telomeres and telomerase in cancer pathogenesis and the aging process. We are usng the telomerase knockout mouse as a modelsystem to understand the role of telomeres in normal development, aging and cancer progression in vivo. This mouse model has revealed that telomeres play an essential role in chromosomal and genomic stability, that telomere erosion elicits very complex cellular responses which ultimately compromises organismal fitness and that telomere function is intimately connected to cancer biology and aging. In addition, we have also learned that telomere dysfunction, coupled with p53 mutation, promotes the formation of carcinomas, the most dominant cancer type in elderly individuals. We are currently using molecular cytogenetic techniques such as spectral karyotyping to characterize the genomes of these carcinomas. Using transgenic and knockout technologies, we will generate additional mouse models of human carcinomas which we expect to faithfully recapitulate the telomere dynamics observed in human cancers.

We are also characterizing a mouse model of premature aging. We have generated compound knockout mice bearing deletions in both the telomerase and Werner gene. In humans, mutations of the Wrn gene leads to Werner Syndrome, a rare autosomal recessive disorder affecting approximately 10 per million individuals. Patients are normal until adolescence, when they develop clinical features of premature aging. Our working hypothesis is that loss of Wrn in the setting of short telomeres results in genomic instability and premature aging in vivo, and we have data supporting this hypothesis. Our long-term goal is to understand pathways and molecules that may be perturbed in the setting of genomic instability, and how these pathways impact on mammalian organismal aging and cancer.

Last updated: 9/24/2009