Hepatic bile secretion is divided into bile salt dependent and independent processes. Canalicular bile flow results from coordinately regulated transport processes located at the sinusoidal sodium/taurocholate transporter and bile canalicular domains of hepatocytes. The applicant and his collaborators have examined the hormonal regulation of the canalicular multidrug resistance associated proteins. The long-range goal of the applicant's laboratory has been to characterize the hormonal regulation of membrane transporters involved in bile formation and to examine the alterations that are involved in the pathogenesis of cholestasis. Studies from the applicant's laboratory indicate that estrogens alter the liver specific expression of the sodium/taurocholate transporter through alterations in secretion of growth hormone. On the other hand, although the multidrug resistance protein is regulated by growth hormone, estrogens alter its expression by posttranslational mechanisms.
The first aim i s to examine the liver-specific expression and growth hormone regulation of the sodium/taurocholate transporter. The applicant will determine whether it is controlled by the interaction of liver specific transcription factors which may be regulated by growth hormone. The human sodium/taurocholate transporter gene has been cloned, and the applicant will characterize the transcription factors involved in its regulation using transfection assays, analysis of protein-protein interactions and mutation of putative domains.
The second aim i s to determine the specific molecular and cellular processes regulating hepatic multidrug-resistance protein 2 at the transcriptional and posttranslational level by pituitary hormones and estrogens, respectively. The applicant will characterize the human promoter, determine the effect of estrogens on its trafficking itinerary and examine the role of putative phosphorylation sites and protein binding domains on posttranslational regulation using intact rats, cell culture models and adenovirus transfections in rats. Taken together, these studies will provide an understanding of the hormonal control of the molecular and cellular events regulating sinusoidal and canalicular transporters that are involved in formation of bile flow and the alterations involved in the pathogenesis of cholestasis.
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