Gizard Post-Doc Fellowship: Role of Telomerase in Macrophage Inflammation and Atherosclerosis

An emerging consensus underscores the importance of inflammation for the development of atherosclerosis, and oxidized LDL (OxLDL) has been identified as a key inductor of macrophage-derived inflammation in atherosclerotic lesions. Whereas many pathways regulating inflammatory gene expression have been characterized, an emerging novel area in vascular biology involves telomerase activation. Telomerase controls key cellular functions including replicative lifespan, cellular senescence and chromatin modifications, differentiation and proliferation. Although telomerase activation in response to injury of the arterial wall has been demonstrated, the role of telomerase in macrophage biology and inflammation remains to be investigated. Telomerase reverse transcriptase (TERT) constitutes the rate-limiting catalytic subunit of telomerase and preliminary data presented in this application demonstrate a previously unrecognized role for TERT in macrophage inflammation. TERT is expressed in macrophages of human atherosclerotic lesions and transcriptionally induced in macrophages in response to proinflammatory stimuli. Further functional studies using macrophages isolated from TERT-deficient mice indicate that TERT promotes IL-1·, iNOS, MCP-1 and MMP-9 gene expression in response to OxLDL. Based on these findings, the central hypothesis of this proposal is that TERT promotes inflammatory gene expression in macrophages thereby contributing to the development of atherosclerosis. To further investigate this hypothesis, we propose 1) To determine the regulation of telomerase in macrophages by proinflammatory stimuli; 2) To determine the role of TERT for macrophage inflammation and to characterize the underlying mechanisms; 3) To determine the role of TERT for the development of atherosclerosis. These experiments may ultimately identify a novel pathway by which macrophage inflammation is regulated and could point to new therapeutic strategies to prevent atherosclerosis development.