DEVELOPMENTAL CONTROL OF INTRODUCED GENES IN RODENTS

这项提案中描述的实验的目的是剖析 影响发育调控的分子机制 内源性小鼠逆转录病毒--小鼠乳腺肿瘤病毒的表达 (MTV)，并将该病毒诱发乳腺癌的作用限制在 乳腺。另一个目标是实现对 决定小鼠是否对MTV易感的遗传因素 乳腺肿瘤和免疫系统在这一过程中的作用。至 实现这些目标，结合分子克隆技术、组织 培养转基因研究和转基因小鼠将被用于 MTV长末端重复序列的DNA序列特征 将病毒直接表达到乳腺。另外， 与这些DNA序列相互作用的转录因子将是 克隆并用于研究这些因子在发育过程中的表达 不同品系小鼠的乳腺和乳腺肿瘤。最后， MTV LTR开放阅读框架(ORF)蛋白的作用，它影响 将评估小鼠的T细胞谱系，在病毒生命的两个阶段 不同品系小鼠对MTV诱导的敏感性 癌症。这项提案中概述的实验将使我们能够 开始剖析遗传背景在肿瘤发生中的作用 MTV启动的过程和免疫系统在应答中的作用 病毒感染和肿瘤发生。进一步说，这些实验将 也增加了我们对这些不同组件的作用的理解 在人类乳腺癌中。

The objective of the experiments described in this proposal is to dissect the molecular mechanisms which affect the developmental regulation of expression of the endogenous murine retrovirus, mouse mammary tumor Virus (MTV) and limit the induction of mammary carcinomas by this virus to the mammary gland. An additional goal is to achieve an understanding of the genetic factors that determine whether mice are susceptible to MTV-induced mammary tumors and the role of the immune system in this process. To achieve these goals, a combination of molecular cloning techniques, tissue culture transfection studies and transgenic mice will be used to characterize the DNA sequences within the long terminal repeat (LTR) of MTV that direct expression of the virus to the mammary gland. Additionally, the transcription factors that Interact with these DNA sequences will be cloned and used to study expression of these factors in the developing mammary gland of different mouse strains and in mammary tumors. Lastly, the role of the MTV LTR open reading frame (ORF) protein, which influences the T cell repertoire in mice, will be assessed, In both the virus life cycle and in the susceptibility of different strains of mice to MTV-induced carcinomas. The experiments outlined in this proposal will allow us to begin to dissect the contributions of genetic background to the tumorigenic process initiated by MTV and the role of the immune system in responding to viral infection and tumorigenesis. By extension, these experiments will also increase our understanding of the role of these different components in human breast cancer.