Oncogenesis by Jaagsiekte Sheep Retrovirus

简介(申请人提供)：肺癌是导致癌症的主要原因 美国的死亡率。细支气管肺泡癌(BAC) 对于高达25%的肺癌；BAC的发病率一直是 增加，而且在病因上与烟草烟雾无关。因此，有 需要在袋子里进行研究。绵羊为BAC提供了一个独特的模型：绵羊肺 由外源性逆转录病毒Jaagsiekte绵羊引起的癌症 逆转录病毒(JSRV)。最近，我们分离出一种具有感染性和致癌性的分子。 JSRV的克隆。JSRV引起OPC的机制引起了人们的极大兴趣。在……里面 初步实验发现，JSRV含有直接转化 DNA转染法测定小鼠NIH3T3细胞的活性。这个 转化活性已定位于JSRV env基因。其他 研究人员已将JSRV细胞受体定位于人类染色体区域 3p21.3，在人类肿瘤中显示杂合性缺失(LOH)的区域， 包括肺癌。这增加了JSRV env蛋白可能 通过结合并干扰血管内皮细胞 肿瘤抑制基因的功能。在拟议的实验中，我们将 探讨JSRV env诱导致癌转化的机制。 具体地说，我们将：1)确定JSRV env蛋白的负责区域 用于转化；2)鉴定与之相互作用的细胞蛋白(S) Env的关键区；3)检测Env蛋白在肿瘤发生中的作用 活体并开发针对这种疾病的转基因小鼠模型；以及4)研究 JSRV env诱导转化的机制。这些实验将给出新的 对JSRV致癌作用的洞察(JSRV是一种重要的兽医疾病 高流行区)，它们可能有助于阐明BAG的发病机制 致癌作用。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer mortality in the United States. Bronchiolo-alveolar carcinoma (BAC) accounts for as much as 25 percent of lung cancer; the incidence of BAC has been increasing, and it is not etiologically linked to tobacco smoke. Thus, there is need for research in BAG. Sheep provide a unique model for BAC: ovine pulmonary carcinoma (OPC) that is caused by an exogenous retrovirus, jaagsiekte sheep retrovirus (JSRV). Recently, we isolated an infectious and oncogenic molecular clone of JSRV. The mechanism by which JSRV causes OPC is of great interest. In preliminary experiments, we have found that JSRV contains direct transforming activity, as measured by DNA transfection assays in murine NIH3T3 cells. The transforming activity has been localized to the JSRV env gene. Other investigators have mapped the JSRV cell receptor to region of human chromosome 3p21.3, an area that shows loss of heterozygosity (LOH) in human tumors, including lung cancer. This raises the possibility that JSRV Env protein may cause oncogenic transformation by binding to, and interfering with, the function of a tumor suppressor gene. In the proposed experiments, we will explore the mechanism of oncogenic transformation induced by JSRV env. Specifically, we will: 1) Identify the region of JSRV Env protein responsible for transformation; 2) Identify the cellular protein(s) that interact with the critical region of Env; 3) Examine the role of Env protein in oncogenesis in vivo and develop transgenic mouse models for the disease; and 4) Study the mechanism of JSRV env-induced transformation. These experiments will give new insights into oncogenesis by JSRV (which is an important veterinary disease in high endemic regions), and they may shed light on the mechanism of BAG oncogenesis.