E-viri
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Glaser, Shannon Stroud
01/2006Dissertation
Cholestatic liver diseases represent a major public health concern leading to liver transplantation or mortality. The role of sensory innervation and neuropeptides in the regulation of liver physiology and cholestatic liver disease pathogenesis has not been studied thoroughly. In our study, we demonstrated that α-CGRP-positive sensory innervation plays a key role in the regulation of cholangiocyte proliferation and biliary mass during cholestasis induced by extrahepatic bile duct obstruction (BDL). We have shown that cholestasis induces proliferation of cholangiocytes with a dramatic increase in biliary mass, which was associated with concomitant increases circulating levels of CGRP. In vitro, α- and β-CGRP stimulated increased intracellular cAMP levels, activation of PKA and phosphorylation of CREB (Ser-133). Finally, we demonstrated that cholangiocyte proliferation induced by cholestasis was partially ablated in a knockout mouse model lacking the sensory neuropeptide α-CGRP. These findings indicate that sensory innervation of the liver plays a predominant role in the regulation of cholangiocyte proliferation and the pathogenesis of cholestatic liver diseases.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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