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: 7440319
• 负责人: ADAM b GLICK
• 金额: $ 24.06万
• 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/7440319
• 关键词: A Mouse; Behavior; Cell Line; Cells; Data; Development; Doxycycline; Dysplasia; Endopeptidases; 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; Range; 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在人类癌症发育中既具有肿瘤抑制剂又具有致癌作用，但是这种功能转换的机制仍然难以捉摸。 TGFBETA1与在RAS等癌细胞中激活的致癌途径的相互作用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，该模型允许对小鼠表皮中TGFBETA1和致癌性RAS的有条件调节。我们发现两种途径的联合表达对血管生成和表皮混乱的协同诱导。这种相互作用在原代角质形成细胞中的转录分析揭示了拮抗和协同反应，反映了肿瘤抑制和肿瘤进展途径。该研究建议的中心假设是，在多阶段致癌过程中，在调节癌细胞表型的RAS和TGFBETA信号通路之间发生了特定的拮抗和协同相互作用。第一个具体目的将检验以下假设：RAS和TGFBETA1的共表达通过检查诱导正常表皮中的两个转基因并监测肿瘤发育而导致快速的恶性肿瘤和转移。具体目标2检查了三重转基因表皮观察到的快速血管生成反应的性质和机制，并测试了在特定AIM1中观察到的肿瘤表型的显着性。具体目标3检验了RAS和TGFBETA1通过改变的基质和连接成分表达的假设破坏表皮的正常结构完整性。特定目标4使用体外原代角质形成细胞模型来检查RAS和TGFBETA1信号通路的分量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。该研究项目的远距离目标是了解RAS与TGFBETA1之间相互作用的分子基础，以便可以设计理性的治疗策略，以阻止这些途径的协同前观察到的相互作用。人类中的癌症是从控制肿瘤细胞行为的逐步激活和信号通路的丧失，与邻近细胞的相互作用，局部微环境和生物的相互作用。在许多人类癌症中，TGFBETA1和RAS途径发生了变化，并且在转移中很重要，该研究项目的远距离目标是了解RAS与TGFBETA1之间相互作用的分子基础，以便可以促进合理的治疗策略，以阻止这些同步的舞会相互作用。