The overall objective is to advance our understanding of the relationship of the Apical Sodium-dependent bile acid transporter (ASBT) and Organic Solute Transporter alpha-beta (OSTa?b?) to the pathogenesis of intestinalandhepatobiliarydisease.Collectively,ourfindingsstronglysupporttheconceptthatinadditionto its essential role in maintaining bile acid (BA) homeostasis, ASBT-OSTa?b? functions to protect the ileal epithelium against BA-induced injury. Moreover, the concept of a protective role for ASBT-OSTa?b? can potentially be extended to other BA-transporting epithelium and the cholehepatic shunt pathway by our identification of a dysfunctional mutation in OSTb? (SLC51B) in two pediatric patients with congenital diarrhea and features of liver disease. However, despite progress, the role of BAs and toxic bile in the pathogenesis of human disease and the opportunities for highly effective therapeutic intervention remain elusive. Guided by the applicants? recently published studies and strong preliminary data, three specific aimsareproposedtointerrogateASBT-OSTa?b??sroleinthepathogenesisofdiseaseandthemechanismof action of new BA-based therapies.
Specific Aim 1 is designed to elucidate the molecular mechanisms underlyingtheilealinjuryassociatedwithinactivationofOSTa?.Thiswillbeaccomplishedbyexaminingthe rolesforBAsandreactiveoxygenspecies(ROS)intheintestinalinjuryandrestitutionresponseinOsta?null mice,andtherolesoftheNox1andNrf2inthatprocess.
SpecificAim2 isdesignedtoelucidatetheroleof theASBTinthecholehepaticshuntingofBAsandtheactionsoftherapeuticandcytotoxicBAs.Thiswillbe accomplishedbyexaminingtherequirementforASBTincholehepaticshuntingofBAs,therequirementfor ASBT in the bicarbonate-rich hypercholeresis induced by therapeutic BAs such as UDCA and norUDCA, and the role of biliary ASBT in models of obstructive cholestasis.
Specific Aim 3 is designed to test the hypothesis that OSTa?b? functions to protect human hepatocytes and/or cholangiocytes from BA-induced injury. This will be accomplished using hepatocyte and cholangiocyte in vitro models. These innovative studies will yield novel insights to the the pathways underlying BA-induced injury and role of cholehepatic shunting of BAs in health and disease, with the goal of translating those insights into new preventive measuresandtreatments.
Theproposedresearchisrelevanttopublichealthbecauseitaddressesanurgentunmetneedtotreatforms of cholestatic liver disease. Medical interventions are under development that target specific bile acid (BA) receptorsorBAenterohepaticcyclingandappeartoprovideclinicalbenefitinPrimaryBiliaryCholangitisand inherited forms of liver disease such as Progressive Familial Intrahepatic Cholestasis. The studies in this proposalwillprovidekeyinsightstotheroleoftheBAtransportersandthecholehepaticshuntpathwayinthe pathogenesisofcholestaticliverdiseaseandthemechanismsofactionofnewBA-basedtherapies,thereby providingalogicalframeworktoacceleratetheirclinicaldevelopmentandimplementation.
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