NEOPLASIA DISORDERS INDUCED BY HTLV-1 IN TRANSGENIC MICE

在过去的十年里，越来越多的证据表明， 逆转录病毒参与多种人类疾病。 的 1978年，人类嗜T淋巴细胞病毒型 1（HTLV-1）和成人T细胞白血病。 尽管已经鉴定出HTLV-1 十几年前，许多关于其致病性的问题， 由于缺乏合适的动物， 模型 该提案的长期目标是确定 HTLV-1在转基因小鼠中诱导恶性肿瘤的调节基因，和 将这些转基因小鼠模型用于理解 人类多阶段致癌的分子机制。 该应用程序由五个具体目标组成：[1]具体目标 的HTLV-1 tax基因诱导小鼠T细胞白血病，目的是 建立一个有用的动物模型来研究T细胞恶性肿瘤; [2]解剖 通过在转基因小鼠中进行缺失分析， 了解其结构与功能的关系， 病毒调节蛋白; [3]相互作用的功能演示 在HTLV-1 tax和雷克斯基因的产物之间， 转基因小鼠中细胞基因的表达和功能; [4] 通过物理方法对细胞基因进行系统调查， 税收抑制导致良性增殖发展 疾病;和[5]细胞基因的鉴定和表征 其次是负责收购的税收转移激活 一种恶性的生长状态。 预计从该提案中衍生的小鼠模型将 促进我们对人类恶性肿瘤的理解， 致癌基因在诱导多阶段癌变中的作用。

Over the past decade, there has been increasing evidence for the involvement of retroviruses in a variety of human diseases. The association was first made in 1978 between human T-lymphotropic virus type 1 (HTLV-1) and adult T-cell leukemia. Despite the identification of HTLV-1 more than ten years ago, many questions related to its pathogenicity in humans have remained unanswered because of the lack of appropriate animal models. The long term goals of this proposal are to define the role of the regulatory genes of HTLV-1 in inducing malignancies in transgenic mice, and to apply these transgenic mouse models toward the understanding of the molecular mechanisms for multistage carcinogenesis in humans. This application is composed of five specific aims: [1] specific targeting of the HTLV-1 tax gene to induce T-cell leukemia in mice for the purpose of deriving a useful animal model to study T-cell malignancies; [2] dissection of the product of the tax gene by deletional analysis in transgenic mice to obtain an understanding of the structure-function relationship of this viral regulatory protein; [3] functional demonstration of the interaction between the products of the HTLV-1 tax and rex genes in the control of the expression and functions of cellular genes in transgenic mice; [4] systematic survey by physical methods of cellular genes whose activation or suppression by tax leads to the development of benign proliferative disorders; and [5] identification and characterization of cellular genes secondary to tax trans-activation which are responsible for the acquisition of a malignant state of growth. It is anticipated that the murine models derived from this proposal will facilitate our understanding of human malignancies by directly addressing the role of cancer-causing genes in inducing multistage carcinogenesis.