NEOPLASIA DISORDERS INDUCED BY HTLV-1 IN TRANSGENIC MICE

在过去的十年里，有越来越多的证据表明 逆转录病毒与多种人类疾病的关系。这个 1978年首次在人类T淋巴细胞病毒类型之间建立联系 1例(HTLV-1)和成人T细胞白血病。尽管发现了HTLV-1 十多年前，与其致病性有关的许多问题 由于缺乏合适的动物，人类一直没有得到回答 模特们。这项提案的长期目标是定义 HTLV-1在转基因小鼠致癌中的调控基因，以及 将这些转基因小鼠模型应用于理解 人类多阶段癌变的分子机制。 本申请由五个具体目标组成：[1]具体目标 HTLV-1Tax基因诱导小鼠T细胞白血病的研究 建立有用的动物模型来研究T细胞恶性肿瘤；[2]解剖 Tax基因产物在转基因小鼠中的缺失分析 了解这一结构与功能的关系 病毒调节蛋白；[3]相互作用的功能演示 HTLV-1 Tax和Rex基因产物在控制HLV-1感染中的作用 转基因小鼠细胞基因的表达和功能； 用物理方法对其激活或激活的细胞基因进行系统调查 税收抑制导致良性增生性病变的发展 以及细胞基因的鉴定和特征。 仅次于负责收购的税务交易激活 一种恶性生长状态。 预计从这一提议中衍生出的小鼠模型将 通过直接处理以下内容来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.