Telomerase in Inflammation and Atherosclerosis

端粒是真核细胞染色体末端的DNA TTAGGG重复序列，端粒被端粒酶稳定，起到保护性封顶和防止降解的作用。干细胞结构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，这显然赋予了无限的寿命，并限制了组织更新的速度。相比之下，大多数人类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。尽管大多数成体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转录受到严格调控，并可在不同类型的细胞中对环境信号的变化做出反应。在人类动脉粥样硬化中，端粒酶被激活，TERT的表达与疾病的严重程度相关；然而，端粒酶激活的机制和可诱导的TERT在动脉粥样硬化中的生理作用仍未被发现。我们的初步研究证实，在动脉粥样硬化发展过程中，TERT在人类动脉粥样硬化病变的巨噬细胞中的表达增加，并激活了端粒酶。提出了两个特定的目标，以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。在特定的目标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，并验证TERT构成巨噬细胞中NFK_B调控的靶基因的假设。在具体目标2中，我们将确定TERT在动脉粥样硬化发展中的作用。最终，这些研究的结果不仅将表征动脉粥样硬化中端粒酶激活的潜在机制，而且还将促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.