HGF and Signaling Pathways in Hepatic Tissue Assembly

HGF 和肝组织组装中的信号通路

• 批准号: 7196476
• 负责人: GEORGE K MICHALOPOULOS
• 金额: $ 28.3万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7196476
• 关键词: Address; Adult; Affect; Animals; Appendix; Applications Grants; Biliary; Cells; Cessation of life; Complex; Cultured Cells; Defect; Development; Dexamethasone; EGF gene; Elements; Embryo; Embryology; Embryonic Development; Epidermal Growth Factor Receptor; Epithelial; Epithelium; Exhibits; Female; Gene Expression; Genes; Genetic; Greater sac of peritoneum; Growth; Hepatic; Hepatic Tissue; Hepatocyte; Histologic; Histology; Implant; In Situ; In Vitro; Interleukin-6; Ligands; Literature; Liver; Liver Regeneration; Liver neoplasms; Maintenance; Mitogens; Modeling; Molecular; Mus; Organ; Organoids; Partial Hepatectomy; Pathway interactions; Pattern; Peritoneal; Portal triad; Primary carcinoma of the liver cells; Primordium; Process; Proto-Oncogene Protein c-met; Purpose; Rate; Research; Role; Secondary to; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Standards of Weights and Measures; Stem cells; Testing; Tissue Model; Tissues; Work; Wound Healing; bile duct; biliary tract; carcinogenesis; cell type; computerized data processing; day; extracellular; implantation; in vivo; insight; methionylmethionine; novel; oval cell; receptor; repaired; size; tool; transcription factor

DESCRIPTION (provided by applicant): The purpose of this grant application is to explore new findings from our work as well as new models recently developed in our lab, in order to understand the mechanisms controlling assembly and formation of liver tissue. Gene array analysis of organoid cultures, composed of reassembled hepatic cellular elements, led to better understanding of the mechanisms by which dexamethasone, HGF and EGF regulate hepatic tissue assembly. We also found, unexpectedly, that in cultures maintained in the absence of dexamethasone HGF and EGF there is high proliferative activity, presumably driven by novel mitogen(s) not predicted from the literature derived from hepatocyte cultures or from whole animal, liver regeneration, models. The focused list of these potential mitogens identified from the gene array analysis will be studied in detail until the signaling molecules regulating this process are determined. After this is accomplished, the role of these mitogens in liver early embryogenesis, overall tissue repair and early carcinogenesis will be studied. We will also pursue further analysis of the role of HGF in liver embryology by utilizing an imported colony of Met -/+ mice, heterozygous for deletion of the HGF receptor (cMet). The livers of Met -/- embryos will be carried out alive further and beyond the day of embryonic lethality and will be studied as embryonic implants in the peritoneal cavity. We have recently developed this model and found out that it allows development and organization of all epithelial elements seen in mature liver including hepatocyte plates and bile ductules, even though mature portal triads do not appear. These studies will finally determine whether embryonic defects seen in livers of HGF -/- and Met -/- mice are primary to the genetic deletions or secondary to the placental anomalies seen in these embryos. The pathways leading to development of biliary ductules in wild type and Met -/- embryo livers after embryonic implantation will also allow determination of the importance of HGF as a key factor for biliary development, an item which has been often postulated but never proven. In addition to mitogenic signals, liver tissue assembly and repair also depends on the capacity of cellular elements to function as tissue restricted facultative stem cells for each other. Biliary cells can transdifferentiate to hepatocytes via the "oval cell" pathway. We have now shown that hepatocytes can transdifferentiate to biliary epithelium, in culture and in the whole animal. This relationship between hepatocytes and biliary epithelium establishes a new paradigm of organ stability in which mature, fully differentiated, cell types can function as "stem cells" for each other The signaling pathways and molecular determinants (growth and transcription factors) regulating this process will be studied in cultures, whole animals and embryonic implants. The above studies will provide insights and better understanding of the dynamics of liver tissue formation and provide paradigms with general applicability to other models of formation and maintenance of complex tissues.

描述（由申请人提供）：本拨款申请的目的是探索我们工作的新发现以及我们实验室最近开发的新模型，以了解控制肝组织组装和形成的机制。对由重新组装的肝细胞元件组成的类器官培养物进行基因阵列分析，可以更好地了解地塞米松、HGF 和 EGF 调节肝组织组装的机制。我们还意外地发现，在不存在地塞米松 HGF 和 EGF 的情况下维持的培养物中存在高增殖活性，这可能是由来自肝细胞培养物或来自整个动物、肝再生、模型的文献中未预测到的新型有丝分裂原驱动的。 。将详细研究从基因阵列分析中鉴定出的这些潜在有丝分裂原的重点列表，直到确定调节该过程的信号分子。完成此任务后，将研究这些有丝分裂原在肝脏早期胚胎发生、整体组织修复和早期癌发生中的作用。我们还将利用进口的 Met -/+ 小鼠（杂合子缺失 HGF 受体 (cMet)）群体，进一步分析 HGF 在肝脏胚胎学中的作用。 Met -/- 胚胎的肝脏将在胚胎致死日之后继续存活，并将作为腹膜腔中的胚胎植入物进行研究。我们最近开发了这个模型，并发现它允许在成熟肝脏中看到的所有上皮元素（包括肝细胞板和胆管）的发育和组织，即使成熟的门静脉三联体不出现。这些研究将最终确定 HGF -/- 和 Met -/- 小鼠肝脏中所见的胚胎缺陷是否是由这些胚胎中所见的基因缺失引起的，还是继发于胎盘异常的。胚胎植入后野生型和 Met -/- 胚胎肝脏中胆管发育的途径也将有助于确定 HGF 作为胆管发育关键因素的重要性，这一点经常被假设但从未得到证实。除了促有丝分裂信号之外，肝组织的组装和修复还取决于细胞元件彼此充当组织限制性兼性干细胞的能力。胆管细胞可以通过“卵圆细胞”途径转分化为肝细胞。我们现在已经证明，在培养物和整个动物中，肝细胞可以转分化为胆管上皮。肝细胞和胆管上皮之间的这种关系建立了器官稳定性的新范式，其中成熟的、完全分化的细胞类型可以彼此充当“干细胞”。调节这一过程的信号传导途径和分子决定因素（生长和转录因子）将是在培养物、整体动物和胚胎植入物中进行了研究。上述研究将为肝组织形成的动力学提供见解和更好的理解，并为复杂组织的形成和维持的其他模型提供普遍适用的范例。