Telomerase in Inflammation and Atherosclerosis

端粒是真核生物染色体末端的DNA TTAGGG重复序列，端粒酶对其起着保护帽的作用，防止其降解。干细胞组成性地过度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，这显然赋予了无限期的寿命，并限制了组织更新的速度。相反，大多数成人体细胞被认为在转录上抑制TERT，导致端粒缩短和细胞衰老。尽管大多数成年细胞表现出较低的基础端粒酶活性，但越来越多的证据表明，TERT转录在各种细胞类型中受到严格调控，并可诱导以响应环境线索的变化。人动脉粥样硬化端粒酶激活，TERT表达与疾病程度相关；然而，端粒酶激活的机制和诱导TERT表达在动脉粥样硬化中的生理作用仍有待发现。我们的初步研究证实，在动脉粥样硬化的发展过程中，巨噬细胞中TERT的表达和端粒酶的激活增加。我们提出了两个特定的目的来探索这些发现的意义，并验证端粒酶在巨噬细胞中被诱导并有助于动脉粥样硬化发展的假设。在Specific Aim 1中，我们将利用细胞和分子方法确定巨噬细胞中TERT活化的转录调控，并验证TERT在巨噬细胞中构成NFk _b调控靶基因的假设。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表征端粒酶在动脉粥样硬化中的激活机制，而且将推进我们对端粒酶在动脉粥样硬化中的作用的理解。

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.