ErbB Signaling in Liver Ontogeny and Regeneration

描述(申请人提供)：我们的长期目标是了解控制肝脏生长、分化和再生的机制。表皮生长因子(EGF)及其同系物可以说是在控制肝脏生长、再生和癌变方面研究最彻底的生长因子。然而，EGF与肝脏的关系比人们想象的要复杂得多，因为我们现在知道有几十个EGF样分子，它们通过四种不同的受体-ErbB蛋白发挥作用。各种各样的信号通过这些受体受到影响，这不仅取决于存在哪些配体，而且取决于哪些受体组合可用于重新招募到信号复合体中。本研究的重点是ErbB受体在肝脏生长和分化中的调节作用。我们已经记录了不同的ErbB信号在胎儿和成人肝脏中的相互作用。我们还发现，强大的肝有丝分裂原HGF通过激活ErbB受体在肝细胞中发挥其增殖作用。这一建议的具体目的是：1.确定ErbB2在肝脏生长和分化调节中的发育作用；2.确定EGF受体在肝脏有丝分裂信号中的作用，以及它的已知作用涉及与ErbB2和ErbB3共同信号的程度；以及3.评估ErbB蛋白作为HGF信号转导的中心作用。朝着这些目标的进展将提高我们对EGF样分子在正常组织中如何发出信号，肝脏如何分化为成人功能形式，以及这些有效的有丝分裂原如何调控再生过程中肝脏质量的戏剧性恢复的理解。肝再生是正常或改变生长调节的其他条件的范例，包括组织肥大、伤口愈合和癌症。除了阐明肝脏生长控制的机制外，我们的研究可能最终有助于从未分化的干细胞中生成成熟的肝细胞，用于移植和人工肝的生成。

DESCRIPTION (provided by applicant): Our long-term goal is to understand the mechanisms that control the growth, differentiation, and regeneration of the liver. Epidermal growth factor (EGF) and its homolgs are arguably the most thoroughly studied growth factors in the control of liver growth, regeneration and carcinogenesis. However, the relationship of EGF to the liver is far more complex than ever imagined, since we now know that there are dozens of EGF-like molecules and that they act through four different receptors, the ErbB proteins. A vast diversification of signaling is affected through these receptors depending not only on which ligands are present, but also upon which combinations of receptors are available for recruitment into signaling complexes. This study focuses on the role played by the ErbB receptors as regulators of growth and differentiation in the liver. We have documented different ErbB signaling interactions in fetal and adult liver. We have also discovered that the potent hepatic mitogen, HGF, exerts its proliferative actions in hepatocytes by activating ErbB receptors. The specific aims of this proposal are to: 1. Define the developmental role of ErbB2 in the regulation of liver growth and differentiation; 2. Define the role of the EGF receptor in mitogenic signaling in the liver and the extent to which it's known effects involve co-signaling with ErbB2 and ErbB3; and 3. Evaluate the central role of ErbB proteins as signal transducers for HGF. Progress toward these aims will improve our understanding of how EGF-like molecules signal in a normal tissue, how the liver differentiates into its adult functional form, and how these potent mitogens regulate the dramatic restoration of liver mass during regeneration. Liver regeneration is a paradigm for other conditions of normal or altered growth regulation, including tissue hypertrophy, wound healing, and cancer. In addition to elucidating the mechanisms of growth control in the liver, our studies may ultimately aid in the generation of mature hepatocytes from undifferentiated stems cells for transplantation and for the generation of artificial livers.