GROWTH REGULATION OF LIVER PROGENITOR CELLS

肝祖细胞的生长调节

• 批准号: 8167907
• 负责人: Jennifer Sanders
• 金额: $ 20.69万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167907
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adult; Alternative Therapies; Cells; Computer Retrieval of Information on Scientific Projects Database; Development; Differentiation and Growth; Engraftment; Epithelial Cells; Exhibits; Fetal Liver; Funding; Grant; Growth; Hepatic; Hepatocyte; Injury; Institution; Laboratories; Lead; Liver; Liver Failure; MAPK8 gene; Malignant neoplasm of liver; Mitogens; Pathway interactions; Patients; Population; Pregnancy; Progenitor Cell Engraftment; Proliferating; Rattus; Regulation; Research; Research Personnel; Resistance; Resources; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Sirolimus; Source; Stem cells; Transplantation; United States National Institutes of Health; Western Blotting; Work; base; c-myc Genes; carcinogenesis; cell type; cholangiocyte; chromatin immunoprecipitation; fetal; fetus cell; human FRAP1 protein; injured; insight; liver transplantation; oval cell; progenitor

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. At present, liver transplantation is the only available treatment for patients with liver failure. Alternative therapies such as hepatocyte transplantation have been sought. Research to date has focused on the identification and isolation of various populations of hepatic cells capable of liver repopulation. These studies have shown that a subpopulation of hepatic epithelial cells derived from the mid-gestation fetal rat are capable of engrafting, proliferating, and differentiating into functional hepatocytes upon transplantation to injured and normal adult rat liver. More recently, oval cells which are activated during liver injury have been shown to differentiate into hepatocytes and cholangiocytes upon transplantation. Although the isolation and engraftment capacity of these cells has been well characterized, the mechanisms controlling their proliferation, growth, and differentiation have not been studied. Based on previous work in our laboratory on liver development in the rat, we hypothesize that oval cells and the subpopulation of fetal cells capable of liver repopulation will exhibit a selective growth advantage, the hallmarks of which will be mitogen-independence, sustained c-Myc activity, and rapamycin resistance. We will address this hypothesis by studying the regulation of key mitogenic pathways involving ERK, phosphatidylinositol 3-kinase (PI3K), Akt and mTOR, JNK and Wnt/b-catenin in these cell types. We will also study the regulation of the c-Myc/Max/Mad network. Western immunoblotting, immunofluoresence, RT-PCR, and chromatin immunoprecipitation will be used to delineate the role of these signaling networks in oval cell and fetal liver progenitor proliferation and growth. The proposed studies may lead to the identification of factors that promote or inhibit liver progenitor cell engraftment and expansion. Furthermore, given the role of oval and liver progenitor cells in hepatic cancer, these studies may provide insight into mechanimsms of hepatic carcinogenesis

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 目前，肝移植是肝衰竭患者唯一可用的治疗方法。 已经寻求替代性疗法，例如肝细胞移植。 迄今为止的研究集中在鉴定和隔离能够肝回生量的肝细胞的各种群体。 这些研究表明，源自妊娠中期胎儿大鼠的肝上皮细胞的亚群能够在移植到受伤和正常的成年大鼠肝脏的受伤和正常的成年大鼠肝脏后将，增殖和分化为功能性肝细胞。 最近，在移植后显示出在肝损伤期间被激活的椭圆形细胞分化为肝细胞和胆管细胞。 尽管这些细胞的隔离和植入能力已经很好地表征了，但尚未研究控制其增殖，生长和分化的机制。 基于我们对大鼠肝发育的先前工作，我们假设椭圆形细胞和能够肝回生量的胎儿细胞的亚群将表现出选择性的生长优势，其标志将是丝裂原独立性，可持续的C-Mycc-Myc活性和雷帕霉素耐药性。我们将通过研究涉及ERK，磷脂酰肌醇3-激酶（PI3K），AKT和MTOR，JNK和WNT/B-catenin的关键有丝分裂途径的调节来解决这一假设。 我们还将研究C-MYC/MAX/MAD网络的调节。 西方免疫印迹，免疫荧光，RT-PCR和染色质免疫沉淀将用于描述这些信号网络在椭圆形细胞和胎儿肝脏祖细胞增殖和生长中的作用。 拟议的研究可能导致鉴定促进或抑制肝脏祖细胞植入和扩张的因素。 此外，鉴于椭圆形和肝祖细胞在肝癌中的作用，这些研究可能会洞悉肝癌的机械。