LIVER REPOPULATION FOR LIVER INJURY AND GENE THERAPY

我们的假设是肝脏再生了实质细胞 将有助于开发新的疗法并提供解决方案的系统 肝脏生物学中的基本问题。我们和其他人已经取得了 通过确定允许的目标，在推进这些目标方面取得重大进展 肝细胞存活和功能的条件，提高肝细胞活性的方法 移植的肝细胞质量，对肝脏基因转移的洞察， 和肝祖细胞的分析。然而，更多的工作是 肝细胞移植临床应用前的必要性 可以进行系统的分析。我们提出了一系列研究 旨在通过以下方式进一步定义肝脏再繁殖的安全性 分析移植细胞在操作过程中的生物分布 增加肝脏再生，改善肝脏的有害变化 细胞移植所产生的宿主肝脏及其作用机制 改善细胞在正常或病变肝脏的植入。我们会 开始分离和鉴定来源于干细胞的祖细胞 并分离出稳定的人胎肝细胞系 分化为肝细胞。为了证明祖先的命运 人类肝细胞，我们将开发新的遗传动物模型，这 将允许对移植细胞的存活进行明确的分析， 分化与人肝细胞感染肝炎 病毒来帮助发展疾病模型。这些系统将允许我们 和其他人开发有效的治疗方法和解决基本问题 关于肝炎病毒持续和复制的机制。 急性和慢性肝病的平行真实动物模型 在人类身上。我们建议的研究的完成将大大推进 肝脏个体发育和分化的基础知识， 肝细胞移植的治疗潜力及其研究进展 新的生物系统。

Our hypothesis has been that liver repopulation with parenchymal cells will help develop novel therapies and provide systems for addressing fundamental questions in liver biology. We and others have made significant progress in advancing these goals by identifying permissive conditions for hepatocyte survival and function, methods to increase the mass of transplanted hepatocytes, insights into hepatic gene transfer, and analysis of hepatic progenitor cells. However, more work is necessary before clinical applications of hepatocyte transplantation could be systematically analyzed. We propose a series of studies directed at further defining the safety of liver repopulation by analyzing transplanted cell biodistributions during manipulations to increase liver repopulation, amelioration of deleterious changes in the host liver emanating from cell transplantation, and mechanisms for improving cell engraftment in the normal or the diseased liver. We will begin to isolate and characterize progenitor cells derived from the fetal human liver and to isolate stable cell lines capable of differentiating into hepatocytes. To demonstrate the fate of progenitor human liver cells, we will develop novel genetic animal models, which will allow unequivocal analysis of transplanted cell survival, differentiation and human hepatocytes could be infected with hepatitis viruses to help develop models of disease. These systems will allow us and others to develop effective therapies and to address basic questions concerning mechanisms in hepatitis viral persistence and replication. In parallel bonafide animal models of acute and chronic liver disease in humans. Completion of our proposed studies will greatly advance fundamental knowledge of the ontogeny and differentiation of the liver, therapeutic potential of hepatocyte transplantation, and development of novel biological systems.