Papillomavirus E2 as a cervical/anal cancer drug target

乳头瘤病毒 E2 作为宫颈癌/肛门癌的药物靶点

• 批准号: 6915013
• 负责人: JANET L BRANDSMA
• 金额: $ 24.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6915013
• 关键词: apoptosis; cell proliferation; cell senescence; cervix neoplasms; disease /disorder model; gene induction /repression; gene mutation; genetic regulation; genetic transcription; human papillomavirus; laboratory rabbit; oncogenes; oncogenic virus; rabbit papillomavirus; rectum neoplasms; viral carcinogenesis; virus infection mechanism; virus load; virus protein

DESCRIPTION (provided by applicant): The incidence of cervical and anal cancers in AIDS patients has remained substantial despite the introduction of potent antiretroviral therapy. Because these malignancies and their precursors are caused by human papillomavirus (HPV), the best hope for treatment in AIDS patients lies with the development of anti-HPV drugs. The HPV E2 protein is a logical target for drug development because it is critical for papillomavirus replication. In addition, it activates transcription of the viral E6/E7 oncogenes that cause cellular proliferation. However, E2 also prevents uncontrolled E6/E7 expression, making the loss of E2 function a critical step for HPV-associated carcinogenesis and raising serious concern over the wisdom of developing anti-E2 drugs. There also are in vitro studies indicating that E2 overexpression may be therapeutic. The most definitive assessment of a target for therapeutic intervention is through animal studies. While the actions of the E2 protein are being intensively studied in vitro, little work is being done in mammalian hosts. The proposed research aims to determine the effects of modulating, by conditional transgenesis, E2 activity in an animal model of papillomavirus-induced disease. Because the only papillomavirus genome that induces papillomas and carcinomas in experimental settings is the cottontail rabbit papillomavirus (CRPV), the CRPV-rabbit model will be used. The specific aims are to create vectors containing a full-length CRPV genome and a tetracycline-regulated E2 transgene. Vectors containing an E2 dominant-negative transgene will be used to determine the effects of E2 inactivation on papilloma growth, histopathology, CRPV DNA copy number, E6/E7 transcription, cellular proliferation and apoptosis. Vectors containing a conditional wild-type CRPV E2 transgene will be used to determine the effects of E2 overexpression.

描述（由申请人提供）：尽管采用了有效的抗逆转录病毒疗法，但艾滋病患者中宫颈癌和肛门癌的发病率仍然很高。由于这些恶性肿瘤及其前兆是由人乳头瘤病毒（HPV）引起的，因此治疗艾滋病患者的最大希望在于开发抗HPV药物。 HPV E2 蛋白是药物开发的合理目标，因为它对于乳头瘤病毒复制至关重要。此外，它还激活导致细胞增殖的病毒 E6/E7 癌基因的转录。然而，E2 还可以防止不受控制的 E6/E7 表达，使得 E2 功能的丧失成为 HPV 相关癌发生的关键步骤，并引发人们对开发抗 E2 药物是否明智的严重担忧。还有体外研究表明 E2 过度表达可能具有治疗作用。对治疗干预目标最明确的评估是通过动物研究。虽然 E2 蛋白的作用正在体外进行深入研究，但在哺乳动物宿主中所做的工作却很少。拟议的研究旨在确定通过条件转基因调节乳头瘤病毒诱发疾病的动物模型中 E2 活性的效果。由于在实验环境中唯一诱导乳头状瘤和癌的乳头状瘤病毒基因组是棉尾兔乳头状瘤病毒（CRPV），因此将使用 CRPV-兔模型。 具体目标是创建包含全长 CRPV 基因组和四环素调节的 E2 转基因的载体。含有 E2 显性失活转基因的载体将用于确定 E2 失活对乳头状瘤生长、组织病理学、CRPV DNA 拷贝数、E6/E7 转录、细胞增殖和细胞凋亡的影响。含有条件野生型 CRPV E2 转基因的载体将用于确定 E2 过度表达的影响。