Development of mosaic mouse models of HCC for genetic interspecies inference

描述(申请人提供)：由于缺乏有效的治疗方法，肝细胞癌(HCC)仍然威胁着人类的健康。肝细胞癌通常是慢性肝病与各种危险因素相关的最终结果。此外，非酒精性脂肪性肝炎(NASH)引起的肝细胞癌，被认为是新病例的主要原因，但仍缺乏特征性。虽然已经建立了许多肝癌的小鼠模型，但尚不清楚它们在多大程度上代表了人类肝癌的不同亚群。这项研究计划建议通过建立一个新的体内平台来准确复制小鼠体内人肝癌的体细胞分子图谱，从而改变肝癌动物模型。为此，将通过外显子组测序和基因表达谱对三个独立的肝细胞癌小鼠模型进行详尽的表征。利用包括机器学习和网络分析在内的生物信息学技术，这些数据集将与来自TCGA和ICGC的人类肝癌数据集进行比较，以识别具有与肝癌小鼠模型相似的体细胞分子特征的患者亚群，以及精炼的最小特征遗传异常集。一个衍生的转座子系统将被用来产生忠实复制人类肝细胞癌基因亚群的镶嵌小鼠模型。这些模型将使1)实验解剖不同的肝细胞癌病因的分子机制，2)系统地评估候选的肝细胞癌治疗方法，3)研究治疗耐药性。这份K99/R00职业发展奖提案描述了一个为期两年的指导和为期三年的独立研究项目，该项目对于Font-Burgada博士作为独立调查员的发展至关重要。Font-Burgada博士在西班牙巴塞罗那大学获得博士学位，是因为他在研究基本的染色质调节和表观遗传机制方面所做的工作。然后他搬到加州大学圣地亚哥分校，在那里他加入了迈克尔·卡林博士的实验室，培训癌症和信号转导的小鼠模型。为了完成这项研究计划，Font-Burgada博士设计了强大的培训和职业发展计划，包括：1-继续指导Michael Karin博士，以获得更多关于肝癌小鼠模型和信号转导方面的专业知识；2-生物信息学方面的培训，特别是在识别癌症驱动因素基因异常的方法方面，以及对小鼠和人类肝癌进行网络比较基因组分析的方法方面的培训，并由加州大学圣迭戈分校医学助理教授Hannah Carter博士进行指导。3-培训新兴转座子载体技术的应用，以产生用于体内致癌途径分析的马赛克小鼠模型。4-在加州大学圣迭戈分校药理学系的支持性学术环境中举办职业发展课程和研讨会，以补充培训计划的其他方面。这项培训计划将由一个顾问委员会监督，该委员会由4名成员组成，他们是癌症小鼠模型和生物信息学方面的导师和共同导师，以及其他专家Inder Verma和Trey Ideker，他们在Font-Burgada博士向独立过渡的关键步骤中提供关键的科学见解和必要的指导。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) remains a menace for human health for the lack of any effective treatment. HCC is usually the end result of chronic liver diseases associated with diverse risk factors. Furthermore, non- alcoholic steatohepatitis (NASH) induced HCC, which is projected to be the leading cause of new cases, remains poorly characterized. Although many mouse models of HCC have been developed, it is unclear how well they represent different subgroups of human HCCs. This research plan proposes to transform HCC animal modeling by establishing a novel in vivo platform to accurately replicate the somatic molecular profiles of human HCC in mice. To do this, three independent HCC mouse models will be exhaustively characterized through exome sequencing and gene expression profiling. Using bioinformatics techniques including machine- learning and network analysis, these datasets will be compared with human HCC datasets from TCGA and the ICGC to identify subgroups of patients with similar somatic molecular profiles to the HCC mouse models as well as refined minimum sets of characteristic genetic aberrations. A derived transposon system will be used to generate mosaic mouse models replicating human HCC genetic subgroups faithfully. These models will enable 1) experimental dissection of the molecular mechanisms underlying distinct etiologies of HCC, 2) systematic assessment of candidate HCC therapies and 3) investigation of therapeutic resistances. This K99/R00 career development award proposal describes a two-year mentored and three-year independent research program essential for the development of Dr. Font-Burgada as an independent investigator. Dr. Font-Burgada received his PhD at University of Barcelona, Spain, for the work he performed to investigate basic chromatin regulatory and epigenetic mechanisms. He then moved to University of California, San Diego where he joined Dr. Michael Karin's laboratory to train in mouse models of cancer and signal transduction. For the accomplishment of this research proposal, Dr. Font-Burgada has designed a strong training and career development plan consisting of: 1- the continued mentorship of Dr. Michael Karin to gain additional expertise in mouse models of HCC and signal transduction, 2- Training in bioinformatics, specifically in methods to identify cancer driver genetic aberrations and network-based approaches for comparative genomic analysis of mouse and human HCCs, to be overseen by co-mentor Dr. Hannah Carter, an Assistant Professor of Medicine, at UCSD. 3- Training in application of emerging transposon vector technologies to generate mosaic mouse models for in vivo analysis of oncogenic pathways. 4- Career development courses and seminars in a supportive academic environment in the Department of Pharmacology at UCSD to complement other aspects of the training program. This training plan will be overseen by an advisory committee comprising 4 members, mentor, co-mentor, and additional experts in mouse models of cancer and bioinformatics, Inder Verma and Trey Ideker, providing key scientific insights and essential guidance in critical steps in Dr. Font-Burgada transition to independence.