MECHANISMS REGULATING REVERSAL OF PREMALIGNANCY

逆转癌前病变的调节机制

• 批准号: 6686793
• 负责人: Priscilla A. Furth
• 金额: $ 20.95万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-15 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6686793
• 关键词: Bax gene /protein; adenocarcinoma; gene induction /repression; genetically modified animals; laboratory mouse; mouse mammary tumor virus; neoplasm /cancer genetics; neoplastic process; nucleic acid repetitive sequence; oncoproteins; p53 gene /protein; preneoplastic state; simian virus 40; tumor antigens; viral carcinogenesis; virus genetics; virus protein

DESCRIPTION: (Adapted from the investigator's abstract) Long-range objective: Establish therapeutic approaches that can be used to treat preneoplastic disease. Reversal of premalignant disease is one goal of cancer prevention treatment programs. Interruption of the malignant process at an early stage is preferable to treating the fully developed, and perhaps metastatic, cancer. While inroads have been made in identifying therapeutic agents for reversal of human malignancy, investigations continue. Mechanism-based preclinical and clinical studies are utilized to identify stages of treatable premalignancy and the most appropriate genetic and cellular targets. This study will test the role of specific genetic mechanisms possibly responsible for reversal of premalignant disease utilizing a unique transgenic mouse model of cancer development. In this model temporal expression of the initiating oncoprotein (Simian Virus SV40 T Antigen (TAg)) is conditionally regulated by the tetracycline responsive gene expression (tet responsive) system and directed to epithelial cells by the mouse mammary tumor virus long terminal repeat (MMTV-LTR). When expression of the oncoprotein is terminated after four months, hyperplasia reverses. In contrast, when oncoprotein expression is terminated after seven months, no reversal of hyperplasia is found. Adenocarcinomas that can metastasize to the lung develop between nine and twelve months of age when TAg expression is not interrupted. Specific accomplishments for this proposal: 1) Establish if p53 and Bax induction are critical genetic pathways for the successful reversal of premalignant disease in the whole animal. 2) Determine why pathways that mediate reversal at an early stage of cancer progression in this model cannot promote reversal at a later stage.

描述：（根据调查员的摘要进行了改编）远程目标： 建立可用于治疗前塑性的治疗方法 疾病。抗态度疾病的逆转是预防癌症的目标之一 治疗计划。早期的恶性过程中断是 比治疗充分发达的癌症甚至转移性癌症的优选。 虽然已经在识别治疗剂逆转方面受到了侵犯 人类恶性肿瘤，调查仍在继续。基于机制的临床前和 利用临床研究来确定可治疗的预现态阶段和 最合适的遗传和细胞靶标。 这项研究将测试可能的特定遗传机制的作用 负责使用独特的转基因逆转前疾病 癌症发展的小鼠模型。在此模型中 启动癌蛋白（Simian病毒SV40 T抗原（TAG））是有条件的 受四环素反应性基因表达（TET响应）调节 系统并通过小鼠乳腺肿瘤病毒直接针对上皮细胞 末端重复（MMTV-LTR）。终止癌蛋白的表达 四个月后，增生逆转。相反，当癌蛋白 表达在七个月后终止，没有增生的逆转 成立。可以转移至肺发育二的腺癌腺瘤 当标签表达不中断时，十二个月大。 该提案的具体成就：1）确定P53和Bax是否 诱导是成功逆转的关键遗传途径 整个动物的疾病前疾病。 2）确定为什么途径 在该模型的癌症进展的早期阶段进行介导逆转 在以后的阶段促进逆转。