PATHOGENESIS OF MESENCHYMAL TUMORS INDUCED BY ASBESTOS

石棉诱发的间质肿瘤的发病机制

• 批准号: 2153399
• 负责人: Agnes B Kane
• 金额: $ 18.55万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-06-15 至 1997-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2153399
• 关键词: asbestos; chemical carcinogenesis; chemical related neoplasm /cancer; disease /disorder model; environment related neoplasm /cancer; laboratory mouse; mesothelioma; model design /development; molecular oncology; neoplastic process; tissue /cell culture; toxicant screening; transfection; transforming growth factors; tumor suppressor genes

DESCRIPTION (Adapted from the investigator's abstract): Exposure to asbestos fibers causes diffuse malignant mesothelioma arising from the pleural, pericardial, or peritoneal linings.The ultimate objective of this research is to identify the cellular and molecular events in the development and progression of malignant mesotheliomas induced by asbestos fibers. The proposed experiments will focus on the role of the TGF-beta growth stimulatory pathway and alterations in the p53 tumor suppressor gene during the preneoplastic and neoplastic stages in a murine model system of asbestos tumorigenesis. It is hypothesized that constitutive activation of the TGF- alpha growth stimulatory pathway is an early step in the development of malignant mesotheliomas, followed by alterations in the p53 tumor suppressor gene during progression from focal to invasive growth. The role of the TGF-alpha growth regulatory pathway in the development of malignant mesothelioma will be assessed in vivo and in vitro. MT42 transgenic mice will be used to test whether overexpression of TGF-alpha accelerates the development of malignant mesotheliomas induced by weekly intraperitoneal injections of asbestos fibers. The correlation between overexpression of TGF- alpha, its receptor (EGF-R), cell proliferation, and specific histopathologic stages in the development of malignant mesothelioma will be assessed. A critical evaluation of the role of TGF-alpha expression during the preneoplastic and neoplastic stages in the development of these tumors will be assessed directly by transfection of sense or antisense TGF-alpha vectors in vitro. The effects of increased or decreased TGF-alpha expression on growth of these transfected cell lines will be determined in vitro and in vivo. p53- deficient mice will be used to determine whether heterozygosity at this gene locus accelerates progression from focal to invasive malignant mesotheliomas. Man-made mineral fibers have been developed and used commercially as asbestos fiber substitutes. Few of these materials have been tested for carcinogenicity because lifetime rodent inhalation studies are technically difficult and expensive. These new transgenic mouse model systems may provide a more rapid, cost-effective screening assay for potentially carcinogenic man- made fibers.

描述(改编自调查人员的摘要)：接触 石棉纤维引起弥漫性恶性间皮瘤 胸膜、心包或腹膜衬里。 这项研究是为了确定细胞和分子事件在 人参皂苷诱发恶性间皮瘤的发生发展 石棉纤维。拟议的实验将重点放在 转化生长因子-β生长刺激通路与P53肿瘤的变化 抑癌基因在宫颈癌前病变和癌前病变中的作用 石棉致瘤的小鼠模型系统。据推测， 转化生长因子-α生长刺激通路的结构性激活是 恶性间皮瘤的早期发展，随后 由P53肿瘤抑制基因的改变引起的 灶性到侵袭性生长。 转化生长因子-α生长调控通路在发育中的作用 恶性间皮瘤的发病率将在体内和体外进行评估。MT42 转基因小鼠将被用来测试转化生长因子-α的过度表达 每周加速恶性间皮瘤的发展 腹膜内注射石棉纤维。两者之间的关联性 转化生长因子-α及其受体(EGF-R)的过度表达，细胞增殖， 和恶性发展过程中特定的组织病理学阶段 将对间皮瘤进行评估。对……作用的批判性评价 转化生长因子-α在乳腺癌前病变和癌前病变中的表达 这些肿瘤的发展将直接通过 正、反义转化生长因子-α载体的体外转染。这个 转化生长因子-α表达增强或降低对人卵巢癌生长的影响 这些转基因细胞系将在体外和体内进行鉴定。 P53基因缺陷的小鼠将被用来确定是否存在杂合性 这个基因位点加速了从局灶性恶性向侵袭性恶性的进展 间皮瘤。 人造矿物纤维已被开发并用于商业用途 石棉纤维替代品。这些材料中很少有经过测试的 致癌性，因为终生啮齿动物吸入研究 技术难度大，成本高。这些新的转基因小鼠模型 系统可以提供一种更快速、更具成本效益的筛查方法 潜在致癌的人造纤维。