ErbB Signaling in Liver Ontogeny and Regeneration

描述（由申请人提供）：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（Epidermal growth factor， EGF）及其同系物可以说是在肝脏生长、再生和癌变控制方面研究最彻底的生长因子。然而，EGF与肝脏的关系远比我们想象的要复杂得多，因为我们现在知道有几十种EGF样分子，它们通过四种不同的受体，即ErbB蛋白起作用。信号的广泛多样化通过这些受体受到影响，这不仅取决于哪些配体存在，而且取决于哪些受体组合可用于招募到信号复合物中。本研究的重点是ErbB受体在肝脏生长和分化中的调节作用。我们已经记录了胎儿和成人肝脏中不同的ErbB信号相互作用。我们还发现肝有丝分裂原HGF通过激活ErbB受体在肝细胞中发挥其增殖作用。本建议的具体目的是：1。明确ErbB2在肝脏生长分化调控中的发育作用；2. 确定EGF受体在肝脏有丝分裂信号传导中的作用，以及其已知作用涉及与ErbB2和ErbB3共同信号传导的程度；和3。评估ErbB蛋白作为HGF信号转导的核心作用。这些目标的进展将提高我们对egf样分子如何在正常组织中发出信号，肝脏如何分化成其成年功能形式，以及这些有效的有丝分裂原如何在再生过程中调节肝脏肿块的戏剧性恢复的理解。肝脏再生是其他正常或改变生长调节条件的范例，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产生成熟的肝细胞用于移植和人工肝脏的产生。

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.