Liver regenration occurs after many types of injury, including metabolic, toxic, infectious, and traumatic injuries. It is thought to influence recovery from acute insults, but also to contribute to the development of cirrhosis and neoplasia when deranged during chronic disease. From studies of the response of experimental animals to partial hepatectomy (PH) it is known to be a highly regulated response that proceeds until the original hepatic mass is restored. Recent studies in knockout mice have provided new information about the specific molecules involved in initiation of regeneration. Still, relatively little information is known about downstream signals involved in initiation, or the signals that very precisely terminate regeneration. Furthermore, there is little known about how liver disease influences the signaling pathways that activate and terminate the regenerative response, how they may be deranged, or whether novel pathways are involved. The long term goal of this grant application is to determine whether the molecular signaling pathways involved in initiation and termination of liver regeneration after PH are also involved in the regenerative response in pediatric liver disease using genetically altered mouse models. Preliminary results using specific antagonists and knockout mice suggest that prostaglandin metabolism, specifically that involving COX-2, is critical for initiating regeneration after PH and may precede the action of the cytokine IL-6 in the regenerative response. Other preliminary results using a knockout mouse suggest that the prapoptotic protein Bid plays a role in terminating regeneration. Finally, the preliminary results provide evidence for the feasibility of generating a novel transgenic mouse model of alpha1-AT deficiency using liver specific, inducible expression of human alpha1-ATZ to study liver regeneration in pediatric liver disease. Further studies using genetically altered mice proposed in this application are designed to provide a basis for novel pharmacologic and cell transplantation strategies for treatment/prevention of pediatric liver diseases.
