Development of mosaic mouse models of HCC for genetic interspecies inference

用于遗传种间推断的 HCC 嵌合小鼠模型的开发

基本信息

批准号：
9394884
负责人：
Joan Font-Burgada
金额：
$ 24.9万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9394884
关键词：
Advisory Committees Animal Model BRAF gene Beauty Bioinformatics Biology California Cancer Etiology Cancer Model Catalogs Cell Culture Techniques Cells Cessation of life Characteristics Chromatin Clinical Comparative Genomic Analysis Complement Complex Data Data Set Development Development Plans Disease Dissection Doctor of Philosophy Drowsiness Drug Targeting Ensure Environment Environmental Exposure Epigenetic Process Etiology Gene Expression Profiling Genetic Geography Health Hepatocyte Heterogeneity High Fat Diet Human Human Pathology Investigation K-Series Research Career Programs Knowledge Label Laboratories Life Expectancy Machine Learning Malignant Neoplasms Medicine Mentors Mentorship Methods Modeling Molecular Molecular Profiling Monitor Mosaicism Mouse Protein Mus Mutate Mutation Network-based Oncogenic Orthologous Gene Pathway Analysis Pathway interactions Patients Pharmacology Phase Phenotype Physiological Population Pre-Clinical Model Primary carcinoma of the liver cells Reproducibility Research Research Personnel Research Proposals Resistance Risk Risk Factors Signal Transduction Somatic Mutation Spain Subgroup Survival Rate System Techniques Technology Testing The Cancer Genome Atlas Therapeutic Training Training Programs Transgenes Translating Universities Viral Vector Work Xenograft Model accurate diagnosis base career development chronic liver disease combinatorial comparative course development design effective therapy exhaustion exome sequencing human disease improved in vivo in vivo Model insight member mouse model neoplastic cell nonalcoholic steatohepatitis novel novel therapeutics pre-clinical professor programs public health relevance response statistics success targeted treatment therapeutic evaluation therapy resistant tool tumor tumor progression vector

项目摘要

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.

描述（由申请人提供）：肝细胞癌（HCC）仍然对缺乏任何有效治疗的人类健康受到威胁。 HCC通常是与不同危险因素相关的慢性肝病的最终结果。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，其特征仍然很差。尽管已经开发了许多HCC的小鼠模型，但尚不清楚它们如何代表人类HCC的不同亚组。该研究计划建议通过建立一个新型的体内平台来改善HCC动物建模，以准确复制小鼠人类HCC的体细胞分子谱。为此，将通过外显子组测序和基因表达分析来详尽地表征三个独立的HCC小鼠模型。使用包括机器学习和网络分析在内的生物信息学技术，将将这些数据集与来自TCGA和ICGC的人类HCC数据集进行比较，以鉴定具有与HCC小鼠模型相似的体细胞分子剖面的亚组以及精制的最小特征遗传差异集。派生的转座子系统将用于生成忠实复制人类HCC遗传亚组的镶嵌小鼠模型。这些模型将启用1）对HCC的不同病因的分子机制的实验解剖，2）候选HCC疗法的系统评估和3）研究治疗抗性。这项K99/R00职业发展奖提案描述了一项为期两年的指导和为期三年的独立研究计划，这对于Font-Burgada博士为独立研究员的发展至关重要。 Font-Burgada博士在西班牙巴塞罗那大学获得博士学位，以研究基本的染色质调节和表观遗传机制的工作。然后，他搬到了加利福尼亚大学圣地亚哥分校，在那里他加入了迈克尔·卡林（Michael Karin）博士的实验室，培训癌症模型和信号转导。为了完成这项研究建议，Font-Burgada博士设计了一项强大的培训和职业发展计划，包括：1-迈克尔·卡林博士的持续指导，以在HCC和信号转导的鼠标模型和信号转导的鼠标模型中获得更多的专业知识，在生物信息学的鼠标模型中获得2-在生物信息方面进行的2-专门针对癌症驱动器驱动器和网络共同分析的方法，专门用于识别基于癌症的驱动因素和人类HICC的方法，以识别鼠标的过度分析。 UCSD医学助理教授汉娜·卡特（Hannah Carter）。 3-在应用新兴转座量矢量技术的应用中训练以生成镶嵌小鼠模型，以用于体内的致癌途径。 4-在UCSD药理学系的支持性学术环境中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负责，由4位成员，导师，同事以及其他专家在癌症和生物信息学的老鼠模型，Inder Verma和Trey Ideker中进行监督，在Font-Burgada过渡到独立性的Font-Burgada Transition中提供了关键的科学见解和重要步骤。