Oncogenesis by Jaagsiekte Sheep Retrovirus

描述（由申请人提供）：肺癌是癌症的主要原因 死亡率在美国。细支气管肺泡癌（BAC） 高达25%的肺癌; BAC的发病率一直是 增加，并且在病因学上与烟草烟雾无关。因此， 需要在BAG中进行研究。绵羊为BAC提供了一种独特的模型：绵羊肺 一种由外源性逆转录病毒引起的癌（OPC），jaagsiekte羊 逆转录病毒（JSRV）。最近，我们分离出一种传染性和致癌性分子， JSRV的克隆。JSRV引起OPC的机制非常有趣。在 初步实验发现，JSRV含有直接转化 活性，如通过鼠NIH 3 T3细胞中的DNA转染测定所测量。的 转化活性定位于JSRVenv基因。其他 研究人员已经将JSRV细胞受体定位到人类染色体的某个区域 3p21.3，一个在人类肿瘤中显示杂合性缺失（洛）的区域， 包括肺癌。这增加了JSRV Env蛋白可能 通过结合和干扰肿瘤细胞， 肿瘤抑制基因的功能。在实验中，我们将 探讨JSRVenv诱导肿瘤转化的机制。 具体而言，我们将：1）鉴定JSRV Env蛋白负责的区域 2）鉴定与转化相关的细胞蛋白质; Env的关键区域; 3）检查Env蛋白在肿瘤发生中的作用， 体内和开发转基因小鼠模型的疾病;和4）研究 JSRV env诱导转化的机制。这些实验将提供新的 深入了解JSRV的肿瘤发生（这是一种重要的兽医疾病， 高流行区），并可能揭示BAG的机制 肿瘤发生

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.