Mechanisms and modifiers of beta-catenin-induced hepatic tumorigenesis

β-连环蛋白诱导的肝脏肿瘤发生的机制和调节因素

• 批准号: 8581216
• 负责人: Kimberley Jane Evason
• 金额: $ 15.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-02 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581216
• 关键词: Adult; Advisory Committees; Animal Model; Apoptosis; Award; BAY 54-9085; Behavior; Biology; CTNNB1 gene; California; Cancer Etiology; Cell Line; Chemicals; Classification; Clinical; Cultured Cells; Drosophila genus; Drug Targeting; Felis catus; Fertilization; Fishes; Gene Expression Regulation; Genes; Genetic; Genetic Models; Goals; Growth; Health; Hepatic; Hepatocarcinogenesis; Hepatocyte; Histology; Human; K-Series Research Career Programs; Knowledge; Lead; Life; Liver; Liver neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Mentors; MicroRNAs; Microarray Analysis; Mission; Modeling; Molecular; Molecular Target; Mus; Mutation; Nature; Organism; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Play; Primary carcinoma of the liver cells; Public Health; Regulation; Research; Research Personnel; Role; San Francisco; Scientist; Signal Pathway; Signal Transduction; Somatic Mutation; Subgroup; System; TACSTD2 gene; Testing; Transcriptional Activation; United States National Institutes of Health; Universities; Xenograft Model; Zebrafish; anticancer research; base; beta catenin; carcinogenesis; career; cell growth; chemotherapeutic agent; disability; genome-wide analysis; improved; in vivo; inhibitor/antagonist; instructor; loss of function; mortality; mouse model; novel; prognostic; public health relevance; research study; therapeutic target; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): This is an application for the K08 Mentored Clinical Scientist Research Career Development Award for Dr. Kimberley Evason, a Clinical Instructor at the University of California, San Francisco. Dr. Evason is establishing herself as a young physician-scientist in the research of primary liver cancer (hepatocellular carcinoma, HCC). This K08 award will provide Dr. Evason with the support necessary to accomplish the following career goals: 1) to gain additional expertise in zebrafish biology and histology; 2) to become knowledgeable in cancer signaling pathways; and 3) to develop proficiency in microRNA analysis. To achieve these goals, Dr. Evason has assembled a multi-disciplinary advisory committee comprised of leading zebrafish experts and cancer researchers. HCC is the third leading cause of cancer-related mortality in the world. A major subgroup of HCC is defined by mutations in the gene encoding ¿-catenin, part of the Wnt signaling pathway. Although the main components and targets of the Wnt pathway are well defined, the mechanisms by which alterations in Wnt/ ¿ - catenin signaling lead to HCC are not completely understood. There are currently no clinically approved drugs that target the Wnt/ ¿-catenin pathway. Dr. Evason's long-term goal is to elucidate molecular mechanisms by which HCC is initiated and progresses. The overall objective of this application is to identify molecular pathways and chemical compounds that influence ¿-catenin driven HCC formation, using zebrafish as a model organism. The central hypothesis of this application is that activated ¿-catenin promotes tumor formation in fish via activation of specific genes, including myc, epcam, lef1, foxo1a, and iqgap2, and regulation of specific microRNAs. Dr. Evason will achieve the objective of this proposal by pursuing the following specific aims: 1) define ways in which ¿-catenin activation promotes liver tumor formation in zebrafish; 2) identify drugs that inhibit ¿-catenin driven liver growth and tumor formation; and 3) investigate microRNAs that mediate ¿-catenin driven liver tumor formation. Dr. Evason has developed a new model of HCC, in which activated ¿-catenin drives liver growth and tumor formation in zebrafish. In Aim 1, Dr. Evason will test the hypothesis that activated ¿-catenin promotes tumor formation via increased expression of specific genes by performing gain- and loss- of-function experiments. She will use a mouse model to test the hypothesis that ¿-catenin-induced zebrafish liver tumors are capable of malignant cellular behaviors. In Aim 2, Dr. Evason will perform a chemical screen to identify drugs that inhibit ¿-catenin driven liver growth. In Aim 3, Dr. Evason will test the hypothesis that specific microRNAs mediate ¿-catenin driven liver tumor formation by performing microRNA expression analysis. This project is relevant to cancer research and the missions of the NIH and NCI because it has the potential to reveal underlying mechanisms as well as potential therapeutic targets for HCC.

描述（由申请人提供）：这是弗朗西斯科加州大学临床讲师金伯利·埃夫森博士K 08指导临床科学家研究职业发展奖的申请。Evason博士在原发性肝癌（肝细胞癌，HCC）的研究中成为一名年轻的医生科学家。该K 08奖项将为Evason博士提供必要的支持，以实现以下职业目标：1）获得斑马鱼生物学和组织学方面的额外专业知识; 2）了解癌症信号通路; 3）熟练掌握microRNA分析。为了实现这些目标，Evason博士组建了一个由领先的斑马鱼专家和癌症研究人员组成的多学科咨询委员会。 HCC是世界上第三大癌症相关死亡原因。HCC的一个主要亚组由编码Wnt信号通路的一部分-连环蛋白的基因突变定义。虽然Wnt通路的主要成分和靶点已经明确，但Wnt/β-连环蛋白信号转导的改变导致HCC的机制还不完全清楚。目前还没有临床批准的靶向Wnt/β-连环蛋白通路的药物。Evason博士的长期目标是阐明HCC启动和进展的分子机制。本申请的总体目标是使用斑马鱼作为模式生物来鉴定影响β-连环蛋白驱动的HCC形成的分子途径和化学化合物。这项应用的中心假设是激活的连环蛋白促进鱼类肿瘤的形成 通过激活特定的基因，包括myc，epcam，lef 1，foxo 1a和iqgap 2，以及调节特定的microRNA。Evason博士将通过追求以下具体目标来实现本提案的目标：1）定义环蛋白激活促进斑马鱼肝脏肿瘤形成的方式; 2）鉴定抑制环蛋白驱动的肝脏生长和肿瘤形成的药物;和3）研究介导环蛋白驱动的肝脏肿瘤形成的微小RNA。Evason博士开发了一种新的HCC模型，其中激活的连环蛋白驱动斑马鱼的肝脏生长和肿瘤形成。在目标1中，Evason博士将通过进行功能获得和丧失实验来验证激活的连环蛋白通过增加特定基因的表达来促进肿瘤形成的假设。她将使用小鼠模型来测试以下假设：连环蛋白诱导的斑马鱼肝肿瘤能够产生恶性细胞行为。在目标2中，Evason博士将进行化学筛选，以确定抑制连环蛋白驱动的肝脏生长的药物。在目标3中，Evason博士将通过进行microRNA表达分析来检验特定microRNA介导β-连环蛋白驱动的肝肿瘤形成的假设。该项目与癌症研究以及NIH和NCI的使命相关，因为它有可能揭示HCC的潜在机制以及潜在的治疗靶点。