MT COBRE: EFFECT OF METAL MIXTURES ON GENE EXPRESSION & CARCINOGENESIS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。间皮瘤是在腹膜、胸膜或心包腔的间皮瘤衬里中形成的肿瘤。有一个很强的联系，石棉暴露，与肿瘤出现在10%的暴露工人和石棉暴露史中约70%至80%的间皮瘤患者。肿瘤的形成机制知之甚少，涉及少量的遗传病变，从而使其逃避正常的细胞生长控制。已发表的报告强烈暗示一小部分肿瘤抑制基因或癌基因参与调节正常细胞生长：特别是视网膜母细胞瘤（Rb）基因，p53基因，p16和p14/ARF基因，和神经纤维瘤病2基因（NF 2）。NF 2和p16/p14 ARF始终被DNA突变灭活，而p53和RB遭受很少的突变，但被其他机制灭活。此外，转化DNA肿瘤病毒SV 40被认为在肿瘤形成中起作用。我们希望更好地了解其中两个基因在灭活p53中的作用：SV 40大T抗原（Tag）和NF 2。我们的假设是，这两个基因有效地靶向p53基因失活。我们的研究设计包括建立体外和体内肿瘤形成模型。这些模型涉及通过病毒递送系统在正常小鼠肺中诱导SV 40 Tag表达或在NF 2敲除小鼠中研究石棉诱导的肿瘤形成。我们将通过体外模型中的细胞转化试验或动物模型中的肿瘤发生率来读出这些遗传变化的结果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mesotheliomas are tumors that form in the mesothelial lining of the peritoneal, pleural or pericardial cavities. There is a strong tie to asbestos exposure, with tumors arising in 10% exposed workers and a history of asbestos exposure in about 70% to 80% of all patients with mesothelioma. Tumors form through poorly understood mechanisms involving a small number of genetic lesions, allowing escape from normal cellular growth control. Published reports strongly implicate a small set of tumor suppressor genes or oncogenes involved in regulating normal cellular growth: specifically the retinoblastoma (Rb) gene, the p53 gene, p16 and p14/ARF genes, and the neurofibromatosis 2 gene (NF2). NF2 and p16/p14ARF are consistently inactivated by mutations in the DNA, while p53 and RB suffer few mutations, but are inactivated by other mechanisms. In addition, a transforming DNA tumor virus, SV40, is thought to play a role in tumor formation. We hope to better understand the role of two of these genes in inactivating p53: SV40 Large T antigen (Tag), and NF2. Our hypothesis is that both genes effectively target the p53 gene for inactivation. Our study design involves creation of in vitro and in vivo models of tumor formation. These models involve either the induction of SV40 Tag expression in normal mouse lung via a viral delivery system or the study of asbestos-induced tumor formation in NF2 knockout mice. We will readout the results of these genetic changes by cellular transformation assays in in vitro models or tumor incidence in animal models.