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Telomerase and cellular aging: Analysis of telomerase RNA structure and the impact of telomerase on miRNA expression.

机译：端粒酶和细胞衰老：端粒酶RNA结构分析和端粒酶对miRNA表达的影响。

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摘要

Human cellular mortality is exquisitely regulated in order to prevent both premature loss of cellular replicative potential, which can lead to complications of aging, and the aberrant immortalization of somatic cells, which is associated with tumorigenesis. Human somatic cells experience a finite term of replication, measured in part by telomere attrition. As human somatic cells divide, their telomeres erode due to the end replication problem. When telomeres become critically short, cells enter an irreversible growth arrest called senescence, marked by accumulation of inflammatory mediators, which ultimately cause cell death. Occasionally, cells bypass senescence and continue dividing despite having critically short telomeres. These cells will encounter a second growth arrest check point called crisis, characterized by robust inflammation and profuse cell death. Rarely, cells evade the impetus to stop dividing imposed by senescence and crisis by activating telomerase and becoming immortalized.;Telomerase is a ribonucleoprotein reverse transcriptase, minimally comprised of an RNA subunit, TR, and a catalytic protein subunit, TERT. Cells expressing high levels of telomerase (such as germline and embryonic stem cells) are immortal. In addition, telomerase is activated in and conveys immortality to about 90% of all cancer cells. The most well understood contribution of telomerase to determining cellular mortality is its role in maintaining/extending telomeres, which offsets induction of replicative senescence.;Despite significant advances in senescence and telomerase biology, a complete understanding of the mechanisms regulating senescence and the mechanisms by which telomerase influences cellular mortality is still lacking. Work presented in this dissertation will provide the first evidence confirming a dramatic conformational change within Tetrahymena telomerase RNA (tTR) upon assembly into the telomerase complex that is essential to facilitating telomerase activity. In addition, work described in Chapter 3 provides the first full microRNA profile for replicatively senescent human foreskin fibroblasts. Finally, experiments described in Chapter 4 demonstrate the ability of telomerase to influence expression of miRNAs that undergo regulated expression during senescence and thereby influence a cell's ability to proliferate. A thorough understanding of these miRNA-regulated senescence pathways, and the mechanisms by which telomerase influences these pathways, will facilitate new approaches to treat aging-related disorders and cancer.
机译：为了防止细胞复制潜能的过早丧失（可能导致衰老的并发症）以及与肿瘤发生有关的体细胞异常永生化，对人类细胞的死亡率进行了严格的调节。人类体细胞经历有限的复制期，部分通过端粒磨损来衡量。当人类体细胞分裂时，由于末端复制问题，其端粒受到侵蚀。当端粒严重缺乏时，细胞进入不可逆的生长停滞期，称为衰老，其特征是炎症介质的积累，最终导致细胞死亡。有时，尽管端粒严重短，但细胞绕过衰老并继续分裂。这些细胞将遇到第二个生长停滞检查点，称为危机，其特征是强烈的炎症和大量细胞死亡。很少有细胞通过激活端粒酶并永生化来逃避衰老和危机所导致的分裂，而端粒酶是一种核糖蛋白逆转录酶，最少由RNA亚基TR和催化蛋白亚基TERT组成。表达高水平端粒酶的细胞（例如种系和胚胎干细胞）是永生的。另外，端粒酶被激活并向所有癌细胞的约90％传递永生性。端粒酶对确定细胞死亡的最广为人知的贡献是它在维持/延长端粒中的作用，这抵消了复制性衰老的诱导。尽管衰老和端粒酶生物学取得了重大进展，对调节衰老的机制及其机制的理解也很深入端粒酶影响细胞死亡率仍然缺乏。本论文提出的工作将提供第一个证据，证明四膜虫端粒酶RNA（tTR）组装入端粒酶复合物后，其构象变化是巨大的，这对促进端粒酶活性至关重要。此外，第3章中描述的工作为复制性衰老的人包皮成纤维细胞提供了第一个完整的microRNA图谱。最后，第4章中描述的实验证明端粒酶影响miRNA的表达的能力，而miRNA的表达在衰老过程中受到调节，从而影响细胞的增殖能力。对这些miRNA调控的衰老途径以及端粒酶影响这些途径的机制的透彻了解将促进治疗与衰老相关的疾病和癌症的新方法。

著录项

  • 作者

    Bonifacio, Laura Naomi.;

  • 作者单位

    The University of North Carolina at Chapel Hill.;

  • 授予单位 The University of North Carolina at Chapel Hill.;
  • 学科 Molecular biology.;Genetics.;Aging.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 125 p.
  • 总页数 125
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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