Hereditary Genetics of Hepatocellular Carcinoma

肝细胞癌的遗传遗传学

• 批准号: 10598810
• 负责人: Kirk J Wangensteen
• 金额: $ 8.1万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598810
• 关键词: Address; Age of Onset; Alcohol consumption; Alternative Splicing; Animal Model; Automobile Driving; Binding; CRISPR-mediated transcriptional activation; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; DDR1 gene; Defect; Development; Environmental Risk Factor; Exposure to; Family Cancer History; Family history of; Funding; Genes; Genetic; Genetic Models; Genetic study; Grant; Hepatitis B; Hepatitis C; Hereditary Neoplastic Syndromes; Human; Inherited; Investigation; Link; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Mentorship; Mus; Parents; Pathway interactions; Patient Care; Pharmacology; Primary carcinoma of the liver cells; RNA Splicing; Risk; Risk Factors; Solid; Toxic Environmental Substances; Training Support; Variant; Virus Diseases; Work; beta catenin; falls; fatty liver disease; genetic association; graduate student; hepatocellular carcinoma cell line; in vivo Model; inhibitor; innovation; mortality; parent grant; parent project; patient subsets; personalized medicine; prevent; targeted treatment; tumorigenesis

PROJECT SUMMARY Hepatocellular Carcinoma (HCC) is a devastating and prevalent cancer of the liver with high rates of mortality. Major risk factors include chronic viral infection (hepatitis B or C), fatty liver disease, alcohol use, and exposure to environmental toxins. A family history of HCC raises the risk by more than 2.5-fold. The parent R01 grant will conduct genetic association studies that are powered to detect clinically meaningful germline variants linked to HCC, and will examine predictors of hereditary cancer syndromes in HCC including age of onset and family history of cancer. It also explores the mechanism of HCC arising from defects in HR-DDR genes, and will determine the implications for targeted therapies. In this Diversity Supplement, we request additional funding to support the thesis work for the graduate trainee. Her proposed work falls within the scope of the parent grant. In this project, we have completed a CRISPR activation screen in mice livers of genes that are upregulated in human HCC. We found that upregulated Clk2 expression can drive the development of HCC. CLK2 is a gene involved in splicing that has been found to be a driver in a number of solid cancers, and early work with inhibitors looks promising. We hypothesize that CLK2 promotes HCC via the WNT/β-catenin pathway and that CLK2 inhibitors could prevent HCC development. We propose to address this hypothesis with the following aims: Aim 1 will investigate whether CLK2 is required for tumorigenesis by performing pharmacological and CRISPR targeting of this genes in HCC cell lines and in vivo models; Aim 2 will examine whether the mechanism of CLK2 in driving tumorigenesis is by binding SRSF1 and SRSF3 to influence alternative splicing. These innovative studies of the genetics of HCC have the potential to personalize therapies for the subset of patients with HCC. The mentee will have a mentorship team of experts in HCC, hereditary genetics, and animal models to complete this investigation. This study has the potential to impact on the care of patients with HCC in the US and worldwide.

项目总结 肝细胞癌是一种严重危害人类健康的常见肝癌，死亡率高。 主要危险因素包括慢性病毒感染(乙肝或丙型肝炎)、脂肪肝、饮酒和接触 环境毒素。有肝细胞癌家族史的人患肝癌的风险增加了2.5倍以上。家长R01奖助金将 进行遗传关联研究，以检测具有临床意义的与 并将检查包括发病年龄和家族在内的肝癌遗传性癌症综合征的预测因素 癌症病史。本研究还探讨了HR-DDR基因缺陷导致肝细胞癌的发生机制。 确定靶向治疗的含义。在这份多样性补编中，我们要求提供额外资金，以 支持毕业实习生的论文工作。她提议的工作属于父母拨款的范围。在……里面 在这个项目中，我们已经在小鼠肝脏中完成了CRISPR激活基因的筛选，这些基因在 人类肝细胞癌。我们发现Clk2表达上调可以推动肝细胞癌的发生发展。CLK2是一种基因 参与剪接，已被发现是许多实体癌症的驱动因素，并早期使用抑制剂 看起来很有希望。我们假设CLK2通过WnT/β-连环蛋白途径促进肝细胞癌的发生 抑制剂可以阻止肝细胞癌的发展。我们建议通过以下目标来解决这一假设：目标 1将通过执行药理学和CRISPR来调查肿瘤发生是否需要CLK2 在肝癌细胞系和活体模型中靶向该基因；Aim 2将检测CLK2的机制 通过结合SRSF1和SRSF3来影响选择性剪接，从而推动肿瘤的发生。这些创新之处 对肝细胞癌遗传学的研究有可能使部分肝细胞癌患者的个体化治疗成为可能。 受训者将有一个由肝细胞癌、遗传遗传学和动物模型专家组成的导师团队完成 这次调查。这项研究有可能对美国和世界各地的肝细胞癌患者的护理产生影响。