ERK PATHWAYS IN PATHOGENESIS OF MESOTHELIOMA

间皮瘤发病机制中的 ERK 通路

基本信息

批准号：
8133347
负责人：
Brooke Taylor Mossman
金额：
$ 33.47万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8133347
关键词：
Address Aftercare Apoptosis Asbestos CD44 gene Carmustine Cell Proliferation Cell Survival Cells Chrysotile Cisplatin Collaborations Crocidolite Asbestos Data Dominant-Negative Mutation Epithelial Cells Etiology Exposure to Extracellular Signal Regulated Kinases Family Family member Fiber Gene Expression Gene Proteins Growth Hamsters Human Immunochemistry In Vitro Injection of therapeutic agent Link MAPK7 gene Malignant Neoplasms Malignant mesothelioma Mesothelial Cell Mesothelioma Mitogen-Activated Protein Kinases Modeling Modification Mus Neoplasm Metastasis Pathogenesis Pathology Pathway interactions Pattern Pharmaceutical Preparations Phosphorylation Play Prevention Prevention strategy Proto-Oncogene Proteins c-akt RNA Interference Rattus Rodent Role Signal Pathway Simian virus 40 Testing Time Tissue Microarray Transactivation Transcription Factor AP-1 Transfection Xenograft Model analog carcinogenicity cell killing cell transformation chemotherapeutic agent chemotherapy erionite in vivo Model meetings migration outcome forecast programs protein expression response small hairpin RNA tumor vector vector control virology

项目摘要

Extracellular signal regulated kinases, ERK1/2 and ERK5, are activated by asbestos fibers in mesothelial and airway epithelial cells and play critical roles in cell survival. ERK1/2-dependent Fra-1 expression is also linked causally to morphologic transformation of rat mesothelial cells and expression of genes (c-met, cd44) stimulating cell proliferation and migration. We hypothesize that activation of ERK1/2 and ERK5 signaling pathways occur by carcinogenic fibers (asbestos, erionite) in the pathogenesis of human malignant mesothelioma (MM) and are potentiated by SV40 in a co-carcinogenic manner. Recent exciting data also suggest that these survival pathways are activated in MMs after exposure to chemotherapeutic drugs and can be manipulated to achieve increased cell killing. Thus, we also hypothesize that ERK1/2 and ERK5 pathways contribute, alone or cooperatively, to MM cell survival after chemotherapy. In Aim 1, we will test crocidolite and chrysotile asbestos, well-characterized Turkish erionite (see Project 1), and their nonfibrous analogs, alone and with co-exposures to SV40 to determine if ERK1/2, and ERK5 activity, fos/jun family members, and AP-1 transactivation correlate with patterns of transformation and carcinogenicity as determined in the in vitro/in vivo models developed by Dr. Carbone (Core C). In Aim 2, we will use a panel of SV40+ and - MMs from Core B to determine the effects of dominant negative constructs and small hairpin (sh) RNA interference (RNAi) vectors targeting ERK1/2 and ERK5 on parameters of in vitro cell transformation and survival after treatment with Carmustine (BCNU). In collaboration with Dr. Testa (Project 3) we will also determine if the AKT survival pathway is modified in these studies. In Aim 3, a mouse orthotopic model will be used to determine if SV40+ and - MMs stably transfected with shMEKI, shERKS or both constructs before intrapleural injection and administration of Carmustine, have altered growth and metastases. Identifying the pathways of cell survival in the pathogenesis of MMs is highly significant for prevention and treatment of these devastating tumors. This Program Project allows our previous mechanistic studies in rodent mesothelioma models to be validated in human mesotheliomas and provides us with expertise on virology and MM pathology (Dr. Carbone), AKT survival pathways (Dr. Testa) and use of normal human mesothelial and MM cells (Dr. Pass).

细胞外信号调节激酶ERK1/2和ERK5被间皮中的石棉纤维激活和气道上皮细胞，并在细胞存活中起关键作用。 ERK1/2依赖性FRA-1表达也是与大鼠间皮细胞的形态转化和基因表达相关的因果关系（C-Met，CD44）刺激细胞增殖和迁移。我们假设ERK1/2和ERK5信号的激活人类恶性发病机理中的致癌纤维（石棉，erionite）发生途径间皮瘤（MM），并以共同生殖方式通过SV40增强。最近的令人兴奋的数据表明这些生存途径在接触化学治疗药物和可以操纵以增加细胞杀伤。因此，我们还假设ERK1/2和ERK5 途径在化学疗法后单独或合作地对MM细胞存活有贡献。在AIM 1中，我们将测试鳄鱼石和石棉石棉，特征良好的土耳其埃里翁石（请参阅项目1）及其无纤维单独使用类似物和对SV40的共曝光，以确定ERK1/2和ERK5活动是否，FOS/JUN家族成员，AP-1的反式激活与转化和致癌的模式相关在Carbone博士（Core C）开发的体外/体内模型中确定。在AIM 2中，我们将使用一个面板核心B的SV40+和-MMS的元素，以确定主要负面构建体和小发夹（SH）靶向ERK1/2和ERK5的RNA干扰（RNAI）向量对体外细胞的参数用carmustine（BCNU）处理后的转化和存活。与Testa博士合作（项目 3）我们还将确定在这些研究中是否修改了AKT生存途径。在AIM 3中，鼠标原位模型将用于确定SV40+和-MMS是否稳定转染了Shmeki，Cherks或两种结构在胸膜内注射和carmustine的给药之前，都改变了生长和转移。识别MMS发病机理中细胞存活的途径对于预防和治疗这些毁灭性肿瘤。这个程序项目允许我们以前在人间皮瘤中验证的啮齿动物间皮瘤模型的机械研究，并提供我们拥有病毒学和MM病理学专业知识（Carbone博士），AKT生存途径（Testa博士）并使用正常的人间皮细胞和MM细胞（Pass博士）。