Telomerase in Inflammation and Atherosclerosis

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Telomeres, the DNA TTAGGG repeat sequences at the ends of eukaryotic chromosomes, are stabilized by telomerase to serve as protective capping and to prevent degradation. Stem cells constitutively overexpress the catalytic core telomerase reverse transcriptase (TERT) manifesting high levels of telomerase activity, which confers an apparently indefinite lifespan and is rate limiting for tissue renewal. In contrast, the majority of human adult somatic cells are thought to transcriptionally repress TERT resulting in telomere shortening and cellular senescence. Although most adult cells display low basal telomerase activity, mounting evidence indicates that TERT transcription is tightly regulated and inducible in various cell types in response to changes in environmental cues. In human atherosclerosis telomerase is activated and TERT expression correlates with the extent of the disease; however, the mechanisms underlying telomerase activation and the physiological role of inducible TERT expression in atherosclerosis remain to be discovered. Our preliminary studies confirm increased TERT expression in macrophages of human atherosclerotic lesions and telomerase activation during atherosclerosis development. Two specific aims are proposed to explore the significance of these findings and to test the hypothesis that telomerase is induced in macrophages and contributes to the development of atherosclerosis. In Specific Aim 1 we will utilize cellular and molecular approaches to determine the transcriptional regulation of TERT activation in macrophages and test the hypothesis that TERT constitutes a NFk _B-regulated target gene in macrophages. In Specific Aim 2 we will determine the contribution of TERT to the development of atherosclerosis. Ultimately, the results of these studies will not only characterize the mechanisms underlying telomerase activation in atherosclerosis but also advance our understanding of the role of telomerase in atherosclerosis.