EARLY PULMONARY CARCINOGENESIS INDUCED BY JSRV

JSRV 诱发的早期肺癌

• 批准号: 6193492
• 负责人: NICOLE R KRAIPOWICH
• 金额: $ 10.26万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-04 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6193492
• 关键词: Retroviridae; Retroviridae disease; cell proliferation; genetic markers; lung neoplasms; newborn animals; nucleic acid probes; open reading frames; respiratory epithelium; sheep; southern blotting; viral carcinogenesis; virus genetics

DESCRIPTION (Applicant's Description): The long-range goal of Nicole Kraipowich, D.V.M., is to become an independent investigator specializing in animal models for human neoplastic disease. The training toward this goal will include mentored research and coursework leading to the Ph.D. in the Department of Pathology at Colorado State University under the guidance of Dr. James C. DeMartini. The applicant's training will involve investigation of ovine pulmonary carcinoma (OPC), a contagious neoplasm induced by jaagsiekte sheep retrovirus (JSRV) morphologically similar to human bronchioloalveolar carcinoma, a tumor only weakly associated with smoking. To elucidate the role of JSRV in the early oncogenesis of OPC, proposed studies will focus on the initial events that occur after JSRV infection, including identification of target cells for viral infection and proliferation, determination of clonality of proliferating pneumocytes, and in vivo evaluation of proliferative effects o f viral gene products. The central hypothesis is that polyclonal proliferation of alveolar type II cells, Clara cells, or a common progenitor cell is induced by viral gene products. To address this hypothesis, three specific aims will guide our work: (1) To identify the initial pulmonary cell types infected by JSRV. Newborn lambs will be infected with JSRV constructs containing a marker gene and lung cell-specific mRNA probes will be used to identify the target cells for infection. (2) To examine the clonality and identity of proliferating pulmonary epithelial cells and their JSRV infection status. Proliferation will be assayed by nucleotide analogue incorporation and clonality assessed by Southern blot hybridization of lung tumor DNA using JSRV probes. (3) To examine the capacity of JSRV proteins to induce pulmonary epithelial cell proliferaton in vivo. JSRV vectors containing viral gag/pol, orf X and env sequences will be introduced into lambs and lung cell proliferation assessed. The results of these studies will assist in understanding the mechanisms of initiation and progression in this unique model of pulmonary carcinogenesis and may lead to novel strategies for early detection and even prevention of human lung cancer.

描述 （申请人描述）： 妮可的长远目标 Kraipowich，D.V.M.， 是成为一名独立调查员， 人类肿瘤疾病的动物模型。 为实现这一目标而进行的培训 将包括指导研究和攻读博士学位的课程作业在 在科罗拉多州立大学病理学系的指导下， James C. 德马蒂尼 申请人的培训将涉及调查 绵羊肺腺癌（OPC），一种由jaagsiekte诱发的接触性肿瘤 绵羊逆转录病毒（JSRV）与人细支气管肺泡病毒形态相似 癌症，一种与吸烟仅弱相关的肿瘤。 为了阐明 JSRV在OPC早期肿瘤发生中的作用，建议的研究将集中在 JSRV感染后发生的初始事件，包括识别 用于病毒感染和增殖的靶细胞，克隆性的测定 增殖的肺细胞，并在体内评价增殖作用 外来资产 病毒基因产物 核心假设是， 肺泡II型细胞、Clara细胞或共同祖细胞的增殖 细胞被病毒基因产物诱导。 为了解决这个问题，三 具体目标是：（1）确定初始肺细胞 感染JSRV的类型。 新生羔羊将感染JSRV构建体 将使用含有标记基因和肺细胞特异性mRNA探针的 识别感染的靶细胞。 (2)为了检测克隆性， 增殖性肺上皮细胞与JSRV感染关系的研究 status. 将通过核苷酸类似物掺入法测定增殖 和克隆性，通过肺肿瘤DNA的Southern印迹杂交评估， JSRV探针。 (3)为了检查JSRV蛋白诱导肺细胞凋亡的能力， 上皮细胞增殖。 含有病毒gag/pol的JSRV载体， 将orf X和env序列导入羔羊和肺细胞中， 增殖评估。 这些研究的结果将有助于 了解这一独特疾病的启动和进展机制， 肺癌发生模型，并可能导致新的策略， 检测甚至预防人类肺癌。