DISEASE MODELING OF ALCOHOL RELATED HEPATOCELLULAR CARCINOMA USING PATIENT IPSCS

使用患者 IPSCS 对酒精相关肝细胞癌进行疾病建模

• 批准号: 8030259
• 负责人: Yoon Young Jang
• 金额: $ 19.48万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8030259
• 关键词: Alcohol-Related Hepatocellular Carcinoma; Alcoholic Liver Diseases; Alcohols; Apoptosis; Biological Models; Blood Cells; Cell Line; Cell Proliferation; Cells; Characteristics; Chronic; Cirrhosis; Development; Diagnosis; Disease; Disease model; Endoderm; Environmental Risk Factor; Etiology; Event; Excision; Fibroblasts; Figs - dietary; Foundations; Funding Mechanisms; Goals; Grant; Hepatic; Hepatocarcinogenesis; Hepatocyte; Human; Immune; Immunodeficient Mouse; In Vitro; Individual; JAK2 gene; Lead; Liver; Liver Cirrhosis; Liver diseases; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Mus; Mutation; Organ; Patients; Pharmaceutical Preparations; Pluripotent Stem Cells; Prevention; Prevention therapy; Primary carcinoma of the liver cells; Process; Proliferating; Protocols documentation; Recording of previous events; Research Project Grants; Risk Factors; Role; Sampling; Somatic Mutation; Staging; Stem Cell Research; Stem cells; Survival Rate; Technology; Testing; Therapeutic Intervention; Tissues; Transplant Recipients; Transplantation; Tumor Tissue; base; cancer type; cell type; chemotherapy; chronic alcohol ingestion; disease characteristic; established cell line; human embryonic stem cell; improved; in vivo; in vivo Model; induced pluripotent stem cell; innovation; novel; novel therapeutic intervention; postnatal; postnatal human; progenitor; repaired; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Recent progress in human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) research opens up unprecedented opportunities for the development of new strategies to repair and replace organs including liver. It is also highly desirable to establish disease models using patient specific iPS cells derived from the diseased tissues that contain somatic mutations which are not present in other tissues or in healthy individuals. Hepatocarcinogenesis is considered as a multi-step process involving a number of different genetic alterations caused by environmental factors such as alcohol. The accumulated effects ultimately lead to malignant transformation of hepatocytes. The molecular events underlying each step of the process are not fully understood and better model systems are needed to delineate the mechanism. Complimentary to current available models, iPS technology offers unique opportunity to preserve and study cells at various disease stages that lead to hepatocellular carcinoma (HCC). Towards the goal of studying liver diseases using pluripotent stem cells, we have systematically improved reprogramming of human postnatal cells including primary hepatocytes.Importantly, we were able to differentiate iPS cells into early and mature hepatic cells. In this study, we propose to explore the possibility of modeling alcohol related HCC using patient- and disease- specific iPS cells. We plan to generate iPS cell lines from liver tissues of HCC patients with chronic alcohol consumption history. After characterization of these iPS cell lines, we will differentiate them into different stages of hepatic cells, using iPS cells from healthy donors as controls. We will test the hypothesis that the hepatic cells generated from diseased iPS cells possess certain characteristics of the disease (i.e. HCC). In particular, their ability to terminally differentiate, to proliferate and to undergo apoptosis will be determined. We will also initiate transplantation of these iPSC derived hepatic cells into immunodeficient mice to determine the in vivo activity of the cells. Completion of this study will help establish more human HCC relevant, innovative in vitro and in vivo models to systematically study the molecular mechanisms and the contribution of alcohol and other risk factors to different stages of hepatocarcinogenesis. PUBLIC HEALTH RELEVANCE: Completion of this study will help establish more human HCC relevant, innovative in vitro and in vivo models to systematically study the molecular mechanisms and the contribution of alcohol and other risk factors to different stages of hepatocarcinogenesis.

描述（由申请人提供）：人类胚胎干细胞（ESC）和诱导多能干细胞（iPSC）研究的最新进展为开发修复和替代器官（包括肝脏）的新策略开辟了前所未有的机会。还高度期望使用源自患病组织的患者特异性iPS细胞建立疾病模型，所述患病组织含有不存在于其它组织或健康个体中的体细胞突变。肝癌发生被认为是一个多步骤的过程，涉及许多不同的遗传改变所造成的环境因素，如酒精。累积效应最终导致肝细胞的恶性转化。这一过程中每一步的分子事件还没有完全了解，需要更好的模型系统来描述这一机制。iPS技术是对当前可用模型的补充，为保存和研究导致肝细胞癌（HCC）的各种疾病阶段的细胞提供了独特的机会。为了实现利用多能干细胞研究肝脏疾病的目标，我们系统地改进了包括原代肝细胞在内的人类出生后细胞的重编程。重要的是，我们能够将iPS细胞分化为早期和成熟的肝细胞。在这项研究中，我们建议探索使用患者和疾病特异性iPS细胞建模酒精相关HCC的可能性。我们计划从具有慢性饮酒史的HCC患者的肝组织中产生iPS细胞系。在对这些iPS细胞系进行表征后，我们将使用来自健康供体的iPS细胞作为对照，将它们分化为不同阶段的肝细胞。我们将检验由患病iPS细胞产生的肝细胞具有疾病（即HCC）的某些特征的假设。特别地，将确定它们终末分化、增殖和经历细胞凋亡的能力。我们还将开始将这些iPSC衍生的肝细胞移植到免疫缺陷小鼠中，以确定细胞的体内活性。本研究的完成将有助于建立更多与人类肝癌相关的、创新的体外和体内模型，以系统地研究酒精和其他危险因素对肝癌发生不同阶段的分子机制和贡献。 公共卫生关系：本研究的完成将有助于建立更多与人类肝癌相关的、创新的体外和体内模型，以系统地研究酒精和其他危险因素对肝癌发生不同阶段的分子机制和贡献。