Development of mosaic mouse models of HCC for genetic interspecies inference

描述（由申请人提供）：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。HCC通常是与多种危险因素相关的慢性肝脏疾病的最终结果。此外，非酒精性脂肪性肝炎（NASH）诱导的HCC，预计是新病例的主要原因，仍然缺乏特征。尽管已经开发了许多肝癌小鼠模型，但尚不清楚它们如何很好地代表人类肝癌的不同亚群。本研究计划提出通过建立一种新的体内平台，在小鼠体内精确复制人类HCC的体细胞分子谱，从而改变HCC动物模型。为此，三种独立的HCC小鼠模型将通过外显子组测序和基因表达谱进行详尽的表征。利用包括机器学习和网络分析在内的生物信息学技术，将这些数据集与来自TCGA和ICGC的人类HCC数据集进行比较，以确定与HCC小鼠模型具有相似体细胞分子谱的患者亚组，并细化特征遗传畸变的最小集。一个衍生的转座子系统将用于生成忠实地复制人类HCC遗传亚群的马赛克小鼠模型。这些模型将使1)对HCC不同病因的分子机制进行实验解剖，2)对候选HCC治疗方法进行系统评估，3)研究治疗耐药性。这个K99/R00职业发展奖提案描述了一个为期两年的指导和三年的独立研究计划，对于Font-Burgada博士作为独立研究者的发展至关重要。Font-Burgada博士在西班牙巴塞罗那大学（University of Barcelona）获得博士学位，从事研究基本染色质调控和表观遗传机制的工作。随后，他来到加州大学圣地亚哥分校（University of California, San Diego），加入迈克尔·卡琳（Michael Karin）博士的实验室，在小鼠癌症模型和信号转导方面进行培训。为了完成这项研究计划，Font-Burgada博士设计了一个强大的培训和职业发展计划，包括：1-继续接受Michael Karin博士的指导，在小鼠肝细胞癌模型和信号转导方面获得更多的专业知识；2-接受生物信息学方面的培训，特别是在识别癌症驱动基因畸变的方法和基于网络的方法，用于小鼠和人类肝细胞癌的比较基因组分析，由UCSD医学助理教授Hannah Carter博士监督。培训新兴转座子载体技术的应用，以生成用于体内致癌途径分析的马赛克小鼠模型。在加州大学圣地亚哥分校药学系提供支持性学术环境的职业发展课程和研讨会，以补充培训计划的其他方面。该培训计划将由一个咨询委员会监督，该委员会由4名成员、导师、联合导师以及其他癌症小鼠模型和生物信息学专家Inder Verma和Trey Ideker组成，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.