Regulation of telomerase in endothelial cells in vitro and in vivo

端粒酶逆转录酶（Telomerase Reverse Transcriptase，TERT）是一种具有催化功能的端粒酶，除了保留端粒外，还具有非端粒的功能。其中，TERT通过磷酸化、易位和降解进行后调节。降低内皮细胞中的TERT水平的影响导致细胞凋亡增加以及线粒体功能和细胞迁移的降低。近年来的流行病学研究表明，空气污染和作为主要成分的炭黑颗粒物促进了心血管疾病的发生和发展。此外，已证明颗粒降低内皮功能。然而，到目前为止，尚未确定我们永久暴露于其中的颗粒浓度对血管的分子作用机制。我们的初步数据表明，无毒浓度的超细炭黑颗粒降低端粒酶活性。因此，该项目的第一个目的是阐明这些颗粒的无毒剂量如何影响内皮细胞中的TERT及其在前一个资助期（Akt，Src/Yes，Shp-2，eNOS）中确定的调节剂。在第二个目标中，我们将在小鼠中研究这些机制，包括TERT缺陷动物。此外，我们将特别研究炭黑颗粒对体内内皮功能和心肌梗死的作用，并使用TERT缺陷小鼠研究TERT在其中的作用。

Telomerase with its catalytic subunit Telomerase Reverse Transcriptase (TERT) has non-telomeric functions besides its telomere-retaining property. TERT is regulated post-translationally, amongst others, by phosphorylation, translocation and degradation. Influences reducing TERT levels in endothelial cells lead to increased apoptosis and a decrease in mitochondrial function and cell migration. Recent epidemiologic studies show that air pollution and as a major constituent carbon black particles promote the occurrence and progression of cardiovascular diseases. In addition, it was demonstrated that particles reduce endothelial function. However, up to now the molecular mechanisms of action of particle concentrations, which we are exposed to permanently, on the vessels have not been identified. Our preliminary data show that non-toxic concentrations of ultrafine carbon black particles reduce telomerase activity. Therefore, the first aim of this project is to elucidate how non-toxic doses of these particles influence TERT and its regulators identified in the previous funding period (Akt, Src/Yes, Shp-2, eNOS) in endothelial cells. In the second aim we will investigate these mechanisms in mice, including TERT-deficient animals. Furthermore, we will specifically investigate the role of carbon black particles on endothelial function in vivo and on myocardial infarction and therein the role of TERT using TERT-deficient mice.