Telomerase Transport and Targeting

人类端粒酶是一种核糖核蛋白酶，在染色体末端维持端粒， 在大多数正常体细胞中不存在，并且存在于几乎所有癌细胞中。端粒酶激活 诱导细胞永生化，对肿瘤的发展和进展至关重要。因此，在本发明中， 端粒酶活性的抑制为治疗几乎所有的癌症提供了有希望的方法。 为了合理设计有效的抑制剂，需要对端粒酶有更好的了解。在人类中， 端粒酶包括两个功能必需的亚基：RNA亚基（人端粒酶RNA）和RNA亚基（人端粒酶RNA）。 蛋白亚基（人端粒酶逆转录酶）。装配的位置和机理 癌细胞中的酶复合物（可能指示端粒酶的靶向位置和如何靶向端粒酶）并不 {nown.此外，鉴定端粒酶的其他必要成分将提供 ]确定潜在的抑制靶点。 该建议的主要目标是详细了解贩运人口的情况， 端粒酶在细胞中的组装，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。将在非洲爪蟾和 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 原代和癌细胞系）。为了实现我们的目标，我们确定了以下三个具体目标： 目的： 目的1：探讨功能性端粒酶在体内的生物合成途径 目的2：研究端粒酶关键组分在正常人和正常人组织中的定位和运输， 癌细胞 目的3：研制具有抑制肿瘤细胞生长作用的端粒酶核酶

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