Our long term goal is to understand the mechanisms that control the growth, differentiation, and regeneration of liver. Epidermal growth factor (EGF) and its homologs are arguably the most thoroughly-studied growth factors in the control of liver growth, regeneration, and carcinogenesis, but we now know that signaling through the EGF receptor (EGFr) involves its interaction with a family of related receptors, the ErbB proteins. This study focuses on the role played by the ErbB receptors as regulators of growth and differentiation in liver. ErbB interactions have been studied almost exclusively in transformed or genetically altered cells in culture; their relevance to normal biology outside of the central nervous system and cancer cells has been unclear. We believe this proposal to represent a major conceptual reassessment in how EGF and its related growth factors function in one of its most prominent target tissues. We have documented extensive interactions between the EGFr and ErbB2 and ErbB3, but while the EGFr and ErbB3 are continuously expressed during liver development, the hepatic expression of ErbB2 is extinguished postnatally.
The aims of this proposal are to: 1. Define the developmental role of ErbB2 in designating the proliferative or differentiative phenotype of fetal liver; 2. Delineate the ErbB signaling mechanisms that distinguish fetal from adult liver; and 3. To establish the role of ErbB signaling in liver regeneration. 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 the role of these potent mitogens in regulating the dramatic restoration of liver grwoth during regeneration. Liver regeneration is a paradigm for other conditions of normal or altered growth regulation, including tissue hypertrophy, wound healing, cancer, and possibly even normal childhood growth. In addition to elucidating mechanisms of growth control in the liver, our studies may ultimately aid in the generation of mature hepatocytes from undifferentiated precursor cells for transplantation and for generation of artificial livers.
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