Oncogenesis by Jaagsiekte Sheep Retrovirus

Jaagsiekte 绵羊逆转录病毒导致肿瘤发生

• 批准号: 7013152
• 负责人: HUNG Y. FAN
• 金额: $ 30.38万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2007-07-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013152
• 关键词: Retroviridae; genetically modified animals; laboratory mouse; lung neoplasms; sheep; viral carcinogenesis; virus antigen; virus envelope; virus protein; virus related neoplasm /cancer

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.

描述（由申请人提供）：肺癌是癌症的主要原因 美国的死亡率。细支气管肺泡癌 (BAC) 账户 高达 25% 的肺癌； BAC 的发病率 增加，并且与烟草烟雾无关。因此，有 需要对 BAG 进行研究。绵羊为 BAC 提供了独特的模型：绵羊肺 由外源性逆转录病毒 jaagsiekte 羊引起的癌 (OPC) 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 的机制引起了人们的极大兴趣。在 初步实验，我们发现JSRV包含直接变换 活性，通过小鼠 NIH3T3 细胞中的 DNA 转染测定来测量。这 转化活性已定位于 JSRV env 基因。其他 研究人员将 JSRV 细胞受体定位到人类染色体区域 3p21.3，人类肿瘤中显示杂合性缺失（LOH）的区域， 包括肺癌。这提出了 JSRV Env 蛋白可能 通过结合并干扰，引起致癌转化 肿瘤抑制基因的功能。在提议的实验中，我们将 探讨JSRV env诱导致癌转化的机制。 具体来说，我们将： 1) 确定 JSRV Env 蛋白负责的区域 用于转型； 2) 识别与细胞相互作用的细胞蛋白 Env 的临界区； 3) 检查Env蛋白在肿瘤发生中的作用 体内并开发该疾病的转基因小鼠模型； 4）研究 JSRV env诱导转化的机制。这些实验将带来新的 JSRV（这是一种重要的兽医疾病）对肿瘤发生的见解 高流行地区），它们可能有助于阐明 BAG 的机制 肿瘤发生。