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）及其同系物是研究最深入的控制肝脏生长、再生和癌变的生长因子。然而，EGF与肝脏的关系是复杂的，因为我们现在知道有多种EGF样分子，它们通过四种不同的受体，即ErbB蛋白起作用。ErbB酪氨酸激酶的信号传导不仅取决于存在哪些配体，还取决于哪些受体组合被招募到信号复合物中。也有ErbB信号的负调控因子，如酪氨酸磷酸酶和蛋白质，如Ralt，直接与ErbB蛋白复合物。与ErbB蛋白相互作用的其他受体（包括HGF的受体c-Met）的作用也使分析变得复杂。我们和其他人已经表明，c-met需要一个功能性的EGF受体来引发其对运动和有丝分裂的影响。这项资助的重点是ErbB受体作为肝脏生长和分化的调节剂所起的作用。我们已经通过基因靶向建立了肝细胞特异性EGFr、ErbB2和ErbB3缺陷小鼠，并获得了肝细胞特异性c-Met基因缺失小鼠。本研究的具体目的是：1)明确ErbB蛋白和c-Met在正常肝脏和再生肝脏有丝分裂信号传导中的相互作用；2)评价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细胞中产生成熟的肝细胞用于移植和人工肝脏的产生。公共卫生相关性。肝功能衰竭不可避免地会导致死亡，除非病人能得到足够长的医疗支持，使受损的肝脏自行愈合（再生）或接受肝移植。确定肝脏损伤后自我修复的机制是我们实验室的主要目标。对再生的更好理解将使我们能够设计出加速肝脏修复的治疗方法，并可能有助于产生用于移植和人工肝脏生产的肝细胞。这些研究也可能揭示肝癌发展的过程。

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 homologs are the most thoroughly studied growth factors in the control of liver growth, regeneration and carcinogenesis. However, the relationship of EGF to the liver is complex, since we now know that there are multiple EGF-like molecules and that they act through four different receptors, the ErbB proteins. Signaling by ErbB tyrosine kinases depends on not only which ligands are present, but also which combinations of receptors are recruited into signaling complexes. There are also negative regulators of ErbB signaling, such as tyrosine phosphatases and proteins, such as Ralt, that complex directly with the ErbB proteins. This analysis is also complicated by the role of other receptors that interact with the ErbB proteins, including c-Met, the receptor for HGF. We and others have shown that c-met requires a functional EGF receptor to elicit its effects on motility and mitogenesis. This grant focuses on the role played by the ErbB receptors as regulators of growth and differentiation in the liver. We have created hepatocyte- specific EGFr, ErbB2, and ErbB3 deficient mice by gene targeting, and have obtained liver-specific c-Met gene deleted mice. The specific aims of this proposal are to: 1) To define the interactions among the ErbB proteins and c-Met in the mitogenic signaling of the normal and regenerating liver; 2) To evaluate the central role of the ErbB proteins as signal transducers of 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 cells for transplantation and for the generation of artificial livers. PUBLIC HEALTH RELEVANCE. Liver failure inevitably results in death unless the patient can be medically supported long enough to allow the damaged liver to heal itself (regenerate) or receive a liver transplant. Defining the mechanisms by which the liver restores itself after injury is the primary goal of our laboratory. A better understanding of regeneration will allow us to design therapies that accelerate liver repair and may aid in the generation of liver cells for transplantation and for the production of artificial livers. These studies may also shed light on the process by which liver cancers develop.