Grants and Contracts Details
Description
Macrophages are the major cell type infiltrated into atherosclerotic
plaques and play a dominant role in the formation and progression of atherosclerosis,
the leading cause of death in the US. Telomerase reverse transcriptase (TERT) is
known to be actively involved in arterial remodeling through regulating functions of
vascular cells and immune cells. There is no current evidence, however, demonstrating
a role for TERT in the progression of atherosclerosis. In our pilot study, a genetic model
of TERT and low-density lipoprotein receptor (LDLr) double-null mice (TERT-/-LDLr-/-)
displayed less susceptibility to diet-induced atherosclerosis. Consistent with this
phenotype, a suppressed inflammatory response was observed in TERT-deficient
macrophages. Furthermore, TERT activates signal transducer and activator of
transcription 3 (STAT3) and its target inflammatory genes in macrophages. These
preliminary data suggest a previously unrecognized role for TERT in macrophage
biology during atherosclerosis formation. Therefore, the central hypothesis of this
proposal is that TERT activates the STAT3 pathway, inducing pro-inflammatory
macrophages and thereby contributing to the development of atherosclerosis. Two
specific aims are proposed to examine this hypothesis: 1) Insight into the molecular
mechanism through which TERT promotes pro-inflammatory macrophages. 2)
Investigation of the mechanism by which TERT-induced pro-inflammatory macrophage
populations contribute to atherosclerosis formation. The proposed study is the first to
elucidate the function of TERT in the process of atherosclerosis. The results will deepen
the understanding of the transcriptional regulations of TERT in macrophages which
contribute to atherosclerosis formation, and may be further translated to therapeutic
strategies.
Status | Finished |
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Effective start/end date | 7/1/15 → 6/30/17 |
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