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）：这是一份为旧金山加利福尼亚大学临床讲师 Kimberley Evason 博士申请 K08 指导临床科学家研究职业发展奖的申请。Evason 博士正在将自己定位为一名年轻的医生。研究原发性肝癌（肝细胞癌，HCC）的科学家。该 K08 奖项将为 Evason 博士提供实现以下职业目标所需的支持：1) 获得额外收益。斑马鱼生物学和组织学方面的专业知识；2）了解癌症信号通路；3）提高 microRNA 分析的能力。研究人员表示，HCC 是世界上癌症相关死亡的第三大原因，HCC 的一个主要亚组是由编码基因突变定义的。 -连环蛋白，Wnt 信号通路的一部分 虽然 Wnt 通路的主要成分和靶标已明确，但 Wnt/ ¿ 的改变机制。 - 连环蛋白信号传导导致 HCC 的情况尚不完全清楚，目前尚无针对 Wnt/¿ 的临床药物获批。 Evason 博士的长期目标是阐明 HCC 发生和进展的分子机制。该应用的总体目标是确定影响 ¿ 的分子途径和化学化合物。 -连环蛋白驱动 HCC 形成，使用斑马鱼作为模型生物 该应用的中心假设是激活 ¿ -连环蛋白促进鱼类肿瘤形成 通过激活特定基因（包括 myc、epcam、lef1、foxo1a 和 iqgap2）以及特定 microRNA 的调节，Evason 博士将通过追求以下具体目标来实现该提案的目标：1）定义 ¿ -连环蛋白激活促进斑马鱼肝脏肿瘤的形成；2) 鉴定抑制 ¿ -连环蛋白驱动肝脏生长和肿瘤形成；3) 研究介导 ¿ Evason 博士开发了一种新的 HCC 模型，其中激活了 ¿ -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 博士将测试激活 ¿ 的假设。通过进行功能获得和丧失实验，连环蛋白通过增加特定基因的表达来促进肿瘤形成。她将使用小鼠模型来检验这样的假设：连环蛋白诱导的斑马鱼肝脏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 ¿ 的药物。 -连环蛋白驱动肝脏生长 在目标 3 中，Evason 博士将测试特定 microRNA 介导的假设 ¿ -连环蛋白通过执行 microRNA 表达分析来驱动肝脏肿瘤形成，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 的潜在机制和潜在治疗靶点。