Telomerase Transport and Targeting

端粒酶运输和靶向

• 批准号: 6711453
• 负责人: MICHAEL P TERNS
• 金额: $ 24.14万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6711453
• 关键词: DNA damage; RNA binding protein; RNA directed DNA polymerase; Xenopus oocyte; cell cycle; cell migration; crosslink; enzyme activity; enzyme complex; enzyme inhibitors; gel mobility shift assay; growth inhibitors; neoplastic process; polymerase chain reaction; ribozymes; telomerase

DESCRIPTION (provided by applicant): 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 known. Furthermore, identification of additional essential components of telomerase would provide additional potential targets for inhibition. The 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.

描述（由申请人提供）：在大多数正常体细胞细胞中都没有人类端粒酶，即在染色体末端维持端粒的核糖核蛋白酶，几乎所有癌细胞都存在。端粒酶的激活诱导细胞永生化，对于肿瘤的发展和进展至关重要。因此，抑制端粒酶活性为治疗几乎所有癌症提供了有希望的方法。需要更好地了解端粒酶，以使有效的抑制剂合理设计。在人类中，端粒酶包括两个对功能必不可少的亚基：RNA亚基（人端粒酶RNA）和一个蛋白质亚基（人端粒酶逆转录酶）。癌细胞中酶复合物组装的位置和机制（可能表明靶向端粒酶的何处以及如何靶向）。此外，识别端粒酶的其他基本要素将为抑制提供其他潜在的靶标。该提案的主要目标是获得对细胞中端粒酶的运输和组装的详细了解，并开发一类基于RNA的端粒酶抑制剂有效地限制或防止癌细胞的生长。体内分析将在爪蟾卵母细胞（由于系统的许多技术优势）和培养的人类细胞（包括原发性和癌细胞系）中进行。为了解决我们的目标，我们定义了以下三个特定目的：目的1：体内功能端粒酶生物发生的途径2：检查正常和癌细胞中关键人类端粒酶成分的本地化和运输目标3：要开发有效的抗teltelomerase ribozymes，能够预防癌细胞生长。