Mini-Livers Derived from Human IPS Cells for Modeling Steatosis and Therapy

源自人 IPS 细胞的微型肝脏用于脂肪变性建模和治疗

基本信息

批准号：
8897365
负责人：
Alejandro Soto-Gutierrez
金额：
$ 33.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8897365
关键词：
Animal Model Bile Acids Bile Duct Epithelium Blood Vessels Cell Communication Cell model Cells Cessation of life Cirrhosis Cues Cultured Cells Cytochrome P450 Data Deposition Detection Development Disease Early Diagnosis Elements Embryo Employment Engineering Environment Epithelial Cells Evolution Exhibits Fatty Acids Fatty Liver Fatty acid glycerol esters Fibrosis Future Genes Genetic Engineering Glycolysis Goals Health Hepatic Hepatic Tissue Hepatocyte Homeostasis Human Human Development In Vitro Inflammation Inflammatory Insulin Resistance Lead Liver Liver Dysfunction Liver diseases Mediating Messenger RNA Metabolic Metabolic Diseases Metabolism Mitochondria Modeling Molecular Mus Natural History Organ Organ Culture Techniques Organ Model Pathogenesis Pathway interactions Phenotype Prevention approach Primary carcinoma of the liver cells Production Proteins Protocols documentation Public Health Relative (related person)Research Role Stem cells Study models System Tamoxifen Techniques Technology Testing Therapeutic Time Tissue Model Tissues Transplantation Triglycerides Work alternative treatment base cell type cellular engineering disease phenotype improved induced pluripotent stem cell innovation lipid metabolism liver function liver transplantation macrophage nonalcoholic steatohepatitis novel strategies prevent scaffold small hairpin RNA stem stem cell differentiation success three dimensional structure tool

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to develop a natural hepatic scaffold with multi-cellular cues for complete and stable maturation of stem-derived liver cells to engineer functional livers in vitro and use them for modeling liver steatosis and therapeutics. The objectives of the proposed study are to develop an organ culture system for liver engineering with induced pluripotent stem (iPS) cell-derived liver cells, and investigate its employment to understand pathogenesis, natural history and development of early detection tools and treatments for fatty liver diseases. The central hypothesis to be tested here is that the decellularized natural liver scaffold can be extensively repopulated, will provide a stable organ-like environment for the metabolic maturation of iPS derived liver cells, and may be used as an approach to induce formation of functional mini-livers using human wild type iPS cells or iPS cells after genetic engineer for fatty liver disease by knockdown of SIRT1 and/or (key gene implicated with liver steatosis formation). The rationale for the proposed research is that, once human liver tissue with multi-cellular cues can be reproducibly manufactured in vitro with normal and disease phenotypes, development of liver steatosis can be manipulated pharmacologically, resulting in new and innovative approaches to the prevention and treatment of a variety liver disease. The work described here is expected to i) generate a metabolic maturation system for human iPS cell-derived liver cells to form tissue, ii) establish human iPS cells carrying shRNA mediated conditional knockdown of SIRT1 and iii) develop a novel approach for modeling an organ-like environment to determine the role of SIRT1 in human liver steatosis or fatty liver disease. The results of this work will also have a positive impact by establishing the basis and platform for future sophisticated organ engineering techniques that incorporates several different cell types and may lead to development of entire organs in vitro, these techniques could be applied to study other liver diseases (e.g. metabolic diseases) and is expected to be a major contribution to the fields of stem cells engineering and liver steatosis.

描述（由申请人提供）：我们的长期目标是开发自然的肝脚手架，并具有多细胞线索，以使茎来源的肝细胞完全稳定到成熟到在体外设计功能性肝脏，并将其用于对肝脏脂肪变性和疗法进行建模。拟议的研究的目标是开发一种具有诱导多能茎（IPS）细胞衍生的肝细胞的肝脏工程的器官培养系统，并研究其就业，以了解发病机理，自然病史以及对脂肪肝疾病的早期检测工具和治疗方法的发展。这里要检验的中心假设是 decellularized natural liver scaffold can be extensively repopulated, will provide a stable organ-like environment for the metabolic maturation of iPS derived liver cells, and may be used as an approach to induce formation of functional mini-livers using human wild type iPS cells or iPS cells after genetic engineer for fatty liver disease by knockdown of SIRT1 and/or (key gene implicated with liver steatosis formation).拟议的研究的基本原理是，一旦可以通过正常和疾病表型在体外生产具有多细胞提示的人肝组织，就可以通过药理操纵肝脏脂肪变性的发展，从而导致新的和创新的方法来预防和治疗各种肝病。预计此处描述的工作是I）为人IPS细胞衍生的肝细胞形成组织的代谢成熟系统，ii）建立携带shRNA介导的SIRT 1和III的有条件敲低的人IPS细胞）开发了一种新颖的方法，用于建模一种器官样环境，以确定SIRT1在人肝病患者或Fatty Liver病中的作用。这项工作的结果还将通过建立未来复杂的器官工程技术的基础和平台来产生积极的影响，该技术结合了几种不同的细胞类型，并可能导致整个体外器官的发展，这些技术可以应用于研究其他肝脏疾病（例如，代谢性疾病）（例如，代谢性疾病），预计将是对茎细胞塞动型和Liver stestissis的领域的重要贡献。