A Mouse model of TGFbeta1 and ras oncogene interactions

TGFbeta1 和 ras 癌基因相互作用的小鼠模型

• 批准号: 7649555
• 负责人: ADAM b GLICK
• 金额: $ 23.95万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7649555
• 关键词: A Mouse; Behavior; Cell Line; Cells; Data; Development; Doxycycline; Dysplasia; Epidermis; Extracellular Matrix; Gene Expression; Goals; Growth; Human; In Vitro; Malignant Conversion; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Profiling; Monitor; Mus; Nature; Neoplasm Metastasis; Oncogenic; Organism; Pathway interactions; Peptide Hydrolases; Phenotype; Play; Production; Regulation; Research Personnel; Research Project Grants; Research Proposals; Role; Signal Pathway; Signal Transduction; Staging; Testing; Therapeutic; Transcription Factor AP-1; Transduction Gene; Transforming Growth Factor beta; Transgenes; Transgenic Mice; Transgenic Model; Transgenic Organisms; Tumor Suppression; Tumor Suppressor Proteins; angiogenesis; base; cancer cell; cancer therapy; carcinogenesis; in vitro Model; in vivo; in vivo Model; keratinocyte; malignant phenotype; migration; mouse model; neoplastic cell; programs; ras Oncogene; response; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): TGFbeta1 has both tumor suppressor and oncogenic roles in human cancer development, but the mechanisms underlying this switch in function remain elusive. Changing interactions of TGFbeta1 with oncogenic pathways that are activated in cancer cells such as ras may underlie this dual function. We have developed a transgenic mouse model that allows conditional regulation of both TGFbeta1 and oncogenic ras in the mouse epidermis. We find a synergistic induction of angiogenesis and epidermal disorganization by the combined expression of both pathways. Transcriptional profiling of this interaction in primary keratinocytes reveals antagonistic and synergistic responses that reflect both tumor suppression and tumor progression pathways. The central hypothesis of this research proposal is that during multistage carcinogenesis specific antagonistic and synergistic interactions occur between ras and TGFbeta signaling pathways that regulate the phenotype of the cancer cell. The first specific aim will test the hypothesis that coexpression of ras and TGFbeta1 leads to rapid malignancy and metastasis by examining inducing both transgenes in the normal epidermis and monitoring tumor development. Specific Aim 2 examines the nature and mechanism of the rapid angiogenic response observed in the triple transgenic epidermis and tests the significance for tumor phenotypes observed in Specific Aim1. Specific Aim 3 tests the hypothesis that ras and TGFbeta1 disrupt the normal structural integrity of the epidermis through altered matrix and junctional component expression. Specific Aim 4 uses an in vitro primary keratinocyte model to examine how components of ras and TGFbeta1 signaling pathways interact to regulate gene expression associated with tumor suppression and tumor progression. The long-range goals of this research project are to understand the molecular basis of the interaction between ras and TGFbeta1 so that rational therapeutic strategies can be devised that block the synergistic prometastatic interactions of these pathways. Cancer in humans develops through from the stepwise activation and loss of signaling pathways that govern the behavior of the tumor cell, its interaction with neighboring cells, local microenvironment and organism. The TGFbeta1 and ras pathways are altered in many human cancers and synergistic interactions are important in metastases The long-range goals of this research project are to understand the molecular basis of the interaction between ras and TGFbeta1 so that rational therapeutic strategies can be devised that block the synergistic prometastatic interactions of these pathways.

描述（由申请人提供）：TGFbeta1在人类癌症发展中具有抑瘤和致癌作用，但这种功能转换的机制尚不清楚。TGFbeta1与癌细胞（如ras）中激活的致癌途径的相互作用的改变可能是这种双重功能的基础。我们已经开发了一种转基因小鼠模型，允许有条件地调节小鼠表皮中的TGFbeta1和致癌ras。我们发现通过这两种途径的联合表达可以协同诱导血管生成和表皮破坏。原发性角化细胞中这种相互作用的转录谱揭示了反映肿瘤抑制和肿瘤进展途径的拮抗和协同反应。本研究建议的中心假设是，在多阶段癌变过程中，ras和TGFbeta信号通路之间发生特异性拮抗和协同相互作用，调节癌细胞的表型。第一个具体目标是通过检查在正常表皮中诱导转基因和监测肿瘤发展来验证ras和TGFbeta1的共表达导致快速恶性肿瘤和转移的假设。特异性Aim 2研究了在三重转基因表皮中观察到的快速血管生成反应的性质和机制，并测试了特异性Aim1中观察到的肿瘤表型的意义。特异性目的3验证ras和TGFbeta1通过改变基质和连接成分表达破坏表皮正常结构完整性的假设。特异性Aim 4使用体外原代角化细胞模型来研究ras和TGFbeta1信号通路的成分如何相互作用以调节与肿瘤抑制和肿瘤进展相关的基因表达。该研究项目的长期目标是了解ras和TGFbeta1之间相互作用的分子基础，以便设计出合理的治疗策略，阻断这些途径的协同转移性相互作用。人类癌症是通过控制肿瘤细胞行为的信号通路的逐步激活和丧失，以及与邻近细胞、局部微环境和生物体的相互作用而发展起来的。TGFbeta1和ras通路在许多人类癌症中发生改变，协同作用在转移中很重要。本研究项目的长期目标是了解ras和TGFbeta1之间相互作用的分子基础，以便设计合理的治疗策略，阻断这些途径的协同性促转移相互作用。