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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

基本信息

批准号：
8209222
负责人：
Yoon Young Jang
金额：
$ 23.58万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8209222
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 chronic liver disease 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 public health relevance repaired tumor tumor growth tumorigenesis

项目摘要

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换器官（包括肝脏）的新策略提供了前所未有的机会。利用来自病变组织的患者特异性iPS细胞建立疾病模型也是非常可取的，这些病变组织含有在其他组织或健康个体中不存在的体细胞突变。肝癌的发生被认为是一个多步骤的过程，涉及由酒精等环境因素引起的许多不同的遗传改变。累积效应最终导致肝细胞恶性转化。这一过程中每个步骤背后的分子事件尚不完全清楚，需要更好的模型系统来描述其机制。作为现有模型的补充，iPS技术为保存和研究导致肝细胞癌（HCC）的不同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细胞模拟酒精相关HCC的可能性。我们计划从有慢性饮酒史的HCC患者的肝组织中产生iPS细胞系。在鉴定这些iPS细胞系后，我们将把它们分化成不同阶段的肝细胞，使用来自健康供体的iPS细胞作为对照。我们将验证由病变iPS细胞产生的肝细胞具有该疾病（即HCC）的某些特征的假设。特别是，它们最终分化、增殖和凋亡的能力将被确定。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体内，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HCC相关的创新性体外和体内模型，系统研究酒精等危险因素在肝癌发生不同阶段的分子机制和贡献。