DIFFERENTIATING HUMAN ESC TOWARDS HEPATOCYTES

人类 ESC 与肝细胞的分化

• 批准号: 8172617
• 负责人: MARK ALLEN ZERN
• 金额: $ 15.21万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172617
• 关键词: Address; Alternative Therapies; Artificial Liver; Biological Assay; Cell Line; Cell Proliferation; Cell Transplantation; Cells; Computer Retrieval of Information on Scientific Projects Database; Development; Extracellular Matrix; Funding; Genes; Grant; Growth Factor; Hepatocyte; Human; Image; Institution; Lentivirus Vector; Liver; Liver diseases; Morbidity - disease rate; NOD/SCID mouse; Organ; Pharmacology and Toxicology; Proliferating; Proteins; Research; Research Personnel; Resources; Source; Time; Transplantation; United States National Institutes of Health; cell injury; human embryonic stem cell; human embryonic stem cell line; in vivo; innovation; liver transplantation; mortality; mouse model; nonhuman primate

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Treatment of liver disease with orthotopic liver transplantation (OLT) carries considerable morbidity and mortality. Moreover, due to organ shortages, thousands of people die each year without getting transplanted. Therefore, safer and more convenient alternative therapies will benefit many people requiring liver transplantation. An approach that might address this problem is the development of a proliferative cell line that expresses liver-specific genes which could be employed for cell transplantation or for a bioartificial liver. Developing such a line from human embryonic stem cells (hESC) would also provide cells valuable for pharmacology and toxicology studies. A variety of conditions will be empirically assayed to delineate the most effective approach to differentiate the hESC along a hepatocyte lineage. This will include empiric studies of optimizing media, extracellular matrix, and growth factors. The purity of the cells will be enhanced with transduction of liver-specific lentivirus vectors. The purified cells will be characterized with assays of liver-specific gene products, growth factor responsiveness, and potential oncogenicity. To determine whether the cells can engraft, proliferate, and function after transplantation, studies will be conducted in immunodeficient NOD- SCID mouse models of liver cell injury and in nonhuman primates. Innovative imaging approaches will be utilized to assess the viability and proliferation of the cells over time in vivo.

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 原位肝移植（奥尔特）治疗肝病具有相当高的发病率和死亡率。此外，由于器官短缺，每年有数千人在没有得到移植的情况下死亡。因此，更安全，更方便的替代疗法将使许多需要肝移植的人受益。一种可能解决这个问题的方法是开发一种表达肝脏特异性基因的增殖细胞系，该细胞系可用于细胞移植或生物人工肝。从人类胚胎干细胞（hESC）中开发这样一个细胞系也将为药理学和毒理学研究提供有价值的细胞。将根据经验测定各种条件以描绘使hESC沿着肝细胞谱系分化的最有效方法。这将包括优化培养基、细胞外基质和生长因子的经验研究。细胞的纯度将通过肝特异性慢病毒载体的转导而提高。纯化的细胞将通过肝脏特异性基因产物、生长因子反应性和潜在致癌性的测定来表征。为了确定细胞是否可以在移植后植入、增殖和发挥功能，将在肝细胞损伤的免疫缺陷NOD-SCID小鼠模型和非人灵长类动物中进行研究。将利用创新的成像方法来评估体内细胞随时间的活力和增殖。