Telomerase Transport and Targeting

人类端粒酶，一种维持染色体末端端粒的核糖核蛋白酶，是 在大多数正常体细胞中不存在，在几乎所有癌细胞中都存在。端粒酶的激活 诱导细胞永生化，对肿瘤的发生和发展至关重要。因此， 抑制端粒酶活性为治疗几乎所有癌症提供了一种很有前途的方法。 为了合理设计有效的抑制剂，需要对端粒酶有更好的了解。在人类身上， 端粒酶包括两个功能必需的亚基：RNA亚基(人端粒酶RNA)和 蛋白质亚单位(人端粒酶逆转录酶)。汽车的装配位置和装配机构 癌细胞中的酶复合体(它可能表明在哪里以及如何靶向端粒酶)不是 {现在。此外，鉴定端粒酶的其他基本成分将提供 ]其他潜在的抑制目标。 这项建议的主要目标是详细了解贩运和 在细胞中组装端粒酶，并开发一类基于RNA的端粒酶抑制剂 限制或阻止癌细胞的生长。体内分析将在两种非洲爪哇中进行 卵母细胞(由于该系统的许多技术优势)和培养的人类细胞(包括 原代和癌细胞株)。为了实现我们的目标，我们定义了以下三个具体目标 目标： 目的1：探讨功能性端粒酶在体内的生物发生途径 目的2：检测人端粒酶关键成分在正常人和正常人中的定位和运输。 癌细胞 目的3：开发有效的抗端粒酶核酶以防止癌细胞生长

Human telomerase, the ribonucleoprotein enzyme that maintains telomeres at chromosome termini, is absent in most normal somatic cells and is present in nearly all cancer cells. Activation of telomerase induces cellular immortalization and is critical for the development and progression of tumors. Thus, inhibition of telomerase activity offers a promising approach for treating nearly all cancers. A better understanding of telomerase is needed to allow rational design of effective inhibitors. In humans, telomerase includes two subunits essential for function: an RNA subunit (human telomerase RNA) and a protein subunit (human telomerase reverse transcriptase). The location and mechanism of assembly of the enzyme complex in cancer cells (which may indicate where and how to target telomerase) is not {nown. Furthermore, identification of additional essential components of telomerase would provide ]dditional potential targets for inhibition. rhe major objectives of this proposal are to obtain a detailed understanding of the trafficking and assembly of telomerase in cells, and to develop a class of RNA-based telomerase inhibitors effective at limiting or preventing the growth of cancer cells. In vivo analysis will be performed both in Xenopus oocytes (due to the many technical advantages of the system) and cultured human cells (including primary and cancer cell lines). To address our objectives we have defined the following three specific aims: Aim 1: To investigate the pathway of biogenesis of functional telomerase in vivo Aim 2: To examine the localization and trafficking of key human telomerase components in normal and cancer cells Aim 3: To develop efficacious anti-telomerase ribozymes capable of preventing growth of cancer cells