Our understanding of the molecular determinants of bile formation and cholestasis has been greatly enhanced over the past few years as direct consequence of the cloning of hepatobiliary transporter genes. Recent findings indicate that reductions in the expression of transporter genes can lead to cholestasis, and that the underlying mechanisms involve specific down-regulation of transcription. The overall objectives of this proposal are to define the humoral mediators and molecular pathways that transcriptionally regulate hepatobiliary transporter genes. Initial studies will concentrate on expanding our ongoing work on the regulation of one of the best characterized hepatobiliary transporter genes, the basolateral Na+-dependent bile acid co-transporter, ntcp, in order to provide a focused framework to explore the regulation of other critical genes involved in bile formation.
Aim 1. Determine the cellular and molecular contributions leading to endotoxin-induced down-regulation of the ntcp gene.
Aim 2. Determine the molecular signaling pathways and nuclear transactivators that regulate the ntcp gene promoter.
Aim 3. Determine if bile acids themselves regulate the ntcp gene promoter.
Aim 4. Investigate common regulatory pathways of hepatobiliary transporter genes. The limited availability of effective agents to treat cholestatic diseases detailed explorations into avenues of research that could impact upon the design and use of novel therapeutics. Long-range goals include the potential translation of these studies into the development of transcriptionally active compounds (e.g., bile acids or nuclear hormone receptor ligands) adapted towards ameliorating the pathogenesis of cholestasis.
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