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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
AASLD/ALF Liver Scholar Award
UT Southwestern Medical Center, Dallas, Texas
Regulation of biliary secretion and bile formation by the Ca^2+-activated CIˉ channel TMEM16A
Cl- channels in the apical membrane of biliary epithelial cells, or cholangiocytes, provide the driving force for biliary secretion. Dr. Dutta has recently identified a new Cl- channel in biliary epithelium, TMEM16A, which is activated by extracellular nucleotides. These exciting and novel findings identify for the first time a non-CFTR Cl- channel in biliary epithelium that contributes to Ca2+-activated Cl- secretion. In fact, this channel may represent the molecular identity of the long sought after alternate Ca2+-activated Cl- channel. It is proposed that TMEM16A is activated through a series of steps including i) mechanosensitive ATP release, ii) ATP binding to membrane purinergic (P2) receptors in an autocrine and/or paracrine manner, and iii) increases in [Ca2+]i via P2 receptor stimulation.
Collectively these observations support the following working hypothesis: Cholangiocyte mechanosensitive P2-signaling contributes importantly to biliary secretion and bile formation through effects on transepithelial Cl- secretion mediated by TMEM16A. Aims: 1) To characterize the biophysical and molecular properties of the Ca2+-activated Cl- channel, TMEM16A, as an important mediator of Ca2+-sensitive cholangiocyte secretion. 2) To evaluate the intracellular signals linking modulation of intracellular Ca2+ concentration and TMEM16A channel regulation with special attention to the potential roles of calmodulin/CAMKII and Protein kinase C (PKC) signaling pathways. 3) To define the potential role of inflammatory cytokines (interleukins-4, -5) and vasoactive peptides (endothelin-1), which are associated with cholestasis, on cholangiocyte TMEM16A channel expression and function.
Dr. Dutta’s proposal focuses on the significance of previously unrecognized pathways mediating biliary secretion independent of CFTR, which could be targets for novel therapeutic approaches of modulating bile flow and composition.
Thus, Dr. Dutta’s proposal is directly relevant to the treatment of cholestatic liver diseases characterized by impaired cholangiocyte function and secretion and fulfills the mission of the American Liver Foundation to “facilitate, support and research for the treatment and cure of liver disease”
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