After surgical hepatectomy, the remaining hepatic tissue quickly and efficiently proliferates, reconstituting the normal liver mass. Yet, under certain circumstances, for example, In the septic patient, regeneration does not effectively proceed and hepatic failure ensues. Hepatic regeneration Is known to be influenced by the hormonal environment. Evidence derived from recent studies suggests that the important growth hormone prolactin (PRL) is a potent regulator of hepatocyte mitogenesis. More recently, a 'second messenger' of prolactin action, protein kinase C (PKC), has been identified. PKC isoenzymes are modulated by membrane phospholipid products (i.e. diacylglycerol), calcium Ion, and membrane-associated serine protease. Activated PKC and perhaps also Its cleavage product PKM (which is likewise catalytically functional), in turn phosphorylate receptors, elicit gene expression, etc. This proposal seeks to define the roles of PRL and the PKC Isoenzymes in the mitogenesis which follows liver resection. Specifically, the very early (literally, within minutes) biochemical events 'priming' hepatocytes for regeneration will be defined under conditions of hypo- and euprolactinemia. Then, specific steps relating to the PKC activation sequence will be selectively inhibited In order to identify those which are critical to the successful execution of hepatocellular mitogenesis. A unique feature of this proposal is its exploitation of two recently developed models for the rapid, reproducible and efficient quantification of modulators of hepatocellular proliferation: (1) Isolated hepatocyte nuclei, in which prolactin rapidly induces a 300-400 fold activation of protein kinase C and which also respond to other mitogens, e.g. epidermal growth factor; and (2) precision cut liver slices, which maintain viability and biochemical responsiveness for up to several days after harvesting. From these studies an understanding of the first few minutes of liver regeneration, during which hepatocytes are primed for division, will emerge. Manipulating these biochemical events may well allow the successful initiation or augmentation of liver regeneration at times when it might otherwise falter, for example, after surgical resection or in multiple organ failure.
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