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: 8693968
• 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/8693968
• 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Kimberley Evason博士申请K08指导临床科学家研究职业发展奖的申请，她是加州大学旧金山分校的临床讲师。Evason博士是一名从事原发性肝癌（肝细胞癌，HCC）研究的年轻医师兼科学家。这个K08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)培养对microRNA分析的熟练程度。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是世界上癌症相关死亡的第三大原因。HCC的一个主要亚群是由编码-catenin的基因突变定义的，catenin是Wnt信号通路的一部分。尽管Wnt通路的主要成分和靶点已经明确，但Wnt/¿- catenin信号的改变导致HCC的机制尚不完全清楚。目前还没有临床批准的靶向Wnt/¿-catenin通路的药物。Evason博士的长期目标是阐明HCC发生和发展的分子机制。本应用程序的总体目标是确定影响-catenin驱动的HCC形成的分子途径和化合物，使用斑马鱼作为模式生物。这一应用的中心假设是活化的连环蛋白促进鱼类肿瘤的形成