Telomerase in Inflammation and Atherosclerosis

端粒是真核生物染色体末端的DNA TTAGGG重复序列，它被端粒酶稳定化，起到保护性加帽作用，防止降解。干细胞组成型过表达催化核心端粒酶逆转录酶（TERT），表现出高水平的端粒酶活性，其赋予明显不确定的寿命并且限制组织更新的速率。相比之下，大多数人成年体细胞被认为在转录上抑制TERT，导致端粒缩短和细胞衰老。虽然大多数成年细胞显示低的基础端粒酶活性，越来越多的证据表明，在各种类型的细胞中，响应于环境线索的变化，TERT转录受到严格调控和诱导。在人类动脉粥样硬化中，端粒酶被激活，并且TERT表达与疾病的程度相关;然而，动脉粥样硬化中端粒酶激活的潜在机制和可诱导的TERT表达的生理作用仍有待发现。我们的初步研究证实了人类动脉粥样硬化病变巨噬细胞中TERT表达增加以及动脉粥样硬化发展过程中端粒酶激活。提出了两个具体的目标，以探讨这些发现的意义，并测试的假设，端粒酶是诱导巨噬细胞，并有助于动脉粥样硬化的发展。在具体目标1中，我们将利用细胞和分子方法来确定巨噬细胞中TERT激活的转录调控，并测试TERT构成巨噬细胞中NF κ B调节的靶基因的假设。在具体目标2中，我们将确定TERT对动脉粥样硬化发展的贡献。最终，这些研究的结果不仅将描述动脉粥样硬化中端粒酶激活的机制，而且还将促进我们对端粒酶在动脉粥样硬化中作用的理解。

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.