Toxins, pathogenic infection (viral and bacterial), and physical injury to the liver results in a loss of hepatic tissue, triggering a regenerative response to restore liver cell mass. Dysregulation in the repair process can lead to liver failure or liver cancer. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor functionally identified with proliferative processes. The AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) the prototype for a class of compounds responsible for a range of toxic or adaptive endpoints, inhibits liver regeneration following tissue injury thus implicating the AhR in liver repair. Our long-term goal is to understand mechanistically how the AhR contributes to liver homeostasis by regulating cell proliferation, and thereby identify the molecular basis for TCDD-induced disruption of normal biological processes. We hypothesize that the AhR plays an important role in liver homeostasis, in part by regulating progress through G1 phase of the cell cycle in proliferating hepatocytes. The goal of this proposal is to examine the functional relationship between AhR activity and TCDD responsiveness proteins known to regulate hepatocyte proliferation. Specifically, the planned studies will examine the molecular basis and relative contribution of cyclin-dependent kinase 2 (CDK2) inhibition and plasminogen activator inhibitor-1 (PAI-1) expression on liver regeneration. TCDD alters CDK2 activity and PAI-1 expression during liver regeneration, representing distinct intracellular and extracellular (autocrine or paracrine) mechanisms of action that conspire to inhibit the restorative response to injury. Preliminary results also demonstrate that AhR regulation of the PAI-1 gene involves a novel (non-XRE) DNA element that will be characterized in detail. The proposed studies are an extension of currently funded research looking at the AhR in regulating hepatic proliferation in cell culture models, and seeks to build on previous findings using a physiologically relevant (non-transformed) model of cell proliferation. Parallels between humans and mice in the regenerative response, instills confidence that findings generated during these studies will be directly applicable to the human condition. ? ? ?
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