HORMONAL CARCINOGENESIS--MECHANISMS

激素致癌——机制

• 批准号: 2094583
• 负责人: James S Norris
• 金额: $ 16.81万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2094583
• 关键词: RNase protection assay; Retroviridae; androgens; animal genetic material tag; embryo /fetus transplantation; estrogens; genetic markers; genetically modified animals; hamsters; hormone regulation /control mechanism; hormone related neoplasm /cancer; leiomyosarcoma; molecular cloning; northern blottings; nucleic acid sequence; oncogenic virus; provirus; transposon /insertion element; viral carcinogenesis

Between 5-10% of primate and rodent genomes consist of families of repetitive DNA elements of which retroviruses contribute > 15,000 copies. Mobility of endogenous retroviruses has occurred naturally, but neither the mechanisms inducing movement, the extent of movement, nor the genetic side effects (with minor exception) of movement are known. The present proposal will attempt to address these issues with respect to retrotransposition in the Syrian hamster model for androgen-estrogen induced leiomyosarcomas for four reasons: First, Syrian hamsters are genetically similar; second, they exhibit 100% incidence in leiomyosarcoma induction; third, many retroviral LTR's contain hormone response elements that upregulate transcription; fourth, retroviral gene expression has been documented in tumors during the induction process. This highly reproducible hormonal carcinogenesis model presents us with the opportunity to examine the extent of retrotransposition in vivo and because of the unique vectors allows us to select for new integration sites and flanking genomic DNA which may be causally linked to the cancer process. There are four specific aims addressing these interests. SPECIFIC AIM 1 is to clone a number of the more commonly expressed retroviruses expected to have the highest potential for retrotransposition. After characterization these proviruses will be engineered to contain neoGST3 genes and used to create transgenic animals. SPECIFIC AIM 2 is to develop the techniques for creating transgenic hamsters. SPECIFIC AIM 3 is devoted to creating and breeding transgenic animals, carrying out hormonal carcinogenesis protocols, and analyzing retrotransposition. SPECIFIC AIM 4 is to clone genomic DNA flanking sites of retrotransposition and characterize flanking DNA particularly as to its role in cancer. This proposal may have great relevance to cancers occurring in human endocrine target tissues such as the ovary, breast, and prostate because of the presence of > 15,000 largely uncharacterized human retroviral sequences.

5-10% 的灵长类和啮齿类动物基因组由以下家族组成 逆转录病毒贡献超过 15,000 个拷贝的重复 DNA 元件。 内源性逆转录病毒的流动性是自然发生的，但两者都不是 诱导运动的机制、运动的程度，也不是遗传 运动的副作用（除了少数例外）是已知的。 本提案将尝试解决以下方面的问题： 叙利亚仓鼠雄激素-雌激素模型中的逆转录转座 诱发平滑肌肉瘤有四个原因：首先，叙利亚仓鼠 基因相似；其次，它们在平滑肌肉瘤中的发病率为 100% 就职;第三，许多逆转录病毒LTR含有激素反应元件 上调转录；第四，逆转录病毒基因表达 在诱导过程中记录在肿瘤中。这高度 可重复的激素致癌模型向我们展示了 有机会检查体内逆转录转座的程度 由于独特的载体使我们能够选择新的整合 可能与癌症有因果关系的位点和侧翼基因组 DNA 过程。有四个具体目标来解决这些利益。具体的 目标 1 是克隆一些更常见表达的逆转录病毒 预计具有最高的逆转录转座潜力。后 表征 这些原病毒将被设计为包含 neoGST3 基因并用于创造转基因动物。具体目标 2 是开发 创造转基因仓鼠的技术。具体目标 3 致力于 创造和培育转基因动物，进行激素 癌发生方案，并分析逆转录转座。具体目标 图4是克隆逆转录转座的基因组DNA侧翼位点和 表征侧翼 DNA，特别是其在癌症中的作用。这 该提案可能与人类内分泌中发生的癌症有很大关系 靶组织，如卵巢、乳腺和前列腺，因为 存在超过 15,000 个基本上未表征的人类逆转录病毒序列。