The role of Foxl1 in the differentiation of hepatocytes and cholangiocytes

描述(申请人提供)：慢性肝病和肝硬变是美国常见的与疾病相关的死亡原因。超过270万人慢性感染丙型肝炎病毒，140万人感染乙肝病毒 根据疾控中心最近的记录，这是在2010年。尽管最近在治疗丙型肝炎病毒引起的肝纤维化和肝硬变方面取得了进展，但肝移植仍然是治疗终末期肝病的最成功的方法。在人类肝脏再生过程中，成体祖细胞，即肝祖细胞(HPC)或卵圆形细胞，只有在慢性肝损伤时才会出现，以补充胆管细胞和肝细胞。Foxl1是已知的为数不多的在慢性肝损伤小鼠模型中由HPC特异性表达的蛋白质之一。然而，除了属于有翼螺旋转录因子家族外，人们对Foxl1在肝脏再生中的作用知之甚少。这项研究旨在确定Foxl1在上皮细胞分化为功能性肝细胞和胆管细胞过程中的作用。的目标是 第一个目标是确定Foxl1在肝祖细胞分化的哪个时间点 是肝细胞和胆管细胞形成所必需的。HPC将从Foxl1基因缺陷的小鼠中分离出来，并仔细鉴定它们分化为有功能的肝细胞的能力。一旦发现分化缺陷，将在这些时间点分析差异基因表达，以确定由Foxl1控制的肝细胞分化途径。在第二个目标中，来自与肝脏发育关系最密切的组织--胆囊上皮的Foxl1谱系将被分离出来，并测试其向有功能的肝细胞和胆管细胞转分化的可能性。已有报道称，胆囊腺上皮细胞中含有可转分化为肝细胞和胆管细胞的前体细胞，但具体的前体细胞群体尚未明确。这些结果将加深我们对肝祖细胞生物学的了解，特别是 参与它们分化的分子途径。最终，通过这些研究获得的知识将对早期和中期肝病的治疗方法的发展产生广泛的影响。

DESCRIPTION (provided by applicant): Chronic liver disease and cirrhosis are common disease-related causes of death in the United States. Over 2.7 million people were chronically infected with the hepatitis C virus and 1.4 million people were infected with the hepatitis B virus in 2010, according to recent CDC records. Although recent progress has been made in treating liver fibrosis and cirrhosis caused by the hepatitis C virus, liver transplantation remains the mos successful treatment for end-stage liver disease. During human liver regeneration, adult progenitor cells, known as hepatic progenitor cells (HPCs) or oval cells arise only with chronic liver injury to replenish cholangiocytes and hepatocytes. Foxl1 is one of the few proteins known to be expressed specifically by HPCs in mouse models of chronic liver injury. However, aside from belonging to the winged helix transcription factor family, little is known about the role of Foxl1 during liver regeneration. The proposed research aims to determine the role of Foxl1 in the differentiation of epithelial cells into functional hepatocytes and cholangiocytes. The goal of the first aim is to determine at what point during hepatic progenitor cell differentiation Foxl1 is necessary for hepatocyte and cholangiocyte formation. HPCs will be isolated from mice deficient in Foxl1 and carefully characterized for their ability to differentiate into functional hepatocytes. Once defects in differentiation are identified, differential gene expression will be analyzed at those time points to identify hepatocyte differentiation pathways controlled by Foxl1. In the second aim, the Foxl1-lineage from the gallbladder epithelium, the closest developmentally related tissue to the liver, would be isolated and tested for the potential to trans-differentiate into functional hepatocytes and cholangiocytes. Gallbladder epithelial cells have been reported to contain progenitor cells that can trans-differentiate into hepatocyte and cholangiocytes, but the specific progenitor population has not been clearly identified. These results will enhance our understanding of the biology of hepatic progenitor cells, specifically the molecular pathways involved in their differentiation. Ultimately, the knowledge gained by these studies will have a wide-ranging impact on the development of treatments for early and mid-stage liver disease.