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Principal Investigator: Satdarshan Singh Monga
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $615,393
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Chronic cholestasis results from bile secretory defects or impairment of bile flow, and there are few effective
medical therapies available. During the past funding period, we have made significant progress in determining
the multifactorial role of the Wnt/β-catenin pathway in cholestatic liver disease (CLD). We show β-catenin
inhibition decreases bile acid (BA) synthesis, limiting CLD and fibrosis after bile duct ligation. However,
inhibition of β-catenin in the Mdr2 knockout (KO) mice, a model mimicking Primary Sclerosing Cholangitis
(PSC), aggravated rather than alleviated injury. In fact, Mdr2-β-catenin-KO (DKO1) mice more closely
resembled PSC cases than Mdr2 KO, suggesting this might be a clinically relevant model to study biology and
therapeutics for PSC. β-catenin is also a critical component of adherens junctions (AJs), where its loss is
compensated by spontaneous increase in β-catenin. We show that deletion of both β- & γ-catenin from
hepatocytes (HCs) & cholangiocytes (CCs) in DKO2 mice resulted in CLD, failure to thrive, increased BA,
fibrosis, and mortality, and resembled progressive familial intrahepatic cholestasis (PFIC), a pediatric CLD.
Although DKO1 and DKO2 had a disparate underlying basis, they share phenotypic commonalities including
loss of hepatocyte differentiation & acquisition of mesenchymal characteristics; loss of cell polarity; and
pertubations in cell-cell junctions. Intriguingly, none of these events have been studied in great depth in CLD
and cholangiopathies, making our study innovative and significant. Based on these findings, we hypothesize
that our DKO models represent a subset of PSC and PFIC cases which will be validated by transcriptomic
analyses. Regardless of the disease subtype, these mice serve as powerful pre-clinical models for in-depth
mechanistic studies of processes such as cell maturation/differentiation, cell polarity and/or cell-cell
junctions, that are less well investigated and understood in disease pathogenesis. We further posit that
modulating the determinants of key processes such as TGFβ signaling & β-catenin in both HCs & CCs, will not
only provide novel insights into the role of β-catenin in cell polarity and cholangiocyte biology, but might also
have major therapeutic implications in the general context of cholangiopathies. We are proposing 3
independent yet cohesive aims to test our hypothesis. In Aim 1, we will validate the relevance of the DKO1 and
DKO2 models to human CLD subclasses. In Aim2, we will investigate the role of TGFβ in progressive CLD
models associated with β-catenin loss, since both our preclinical models are characterized by increased TGFβ
signaling and ensuing loss of cell polarity with enhanced expression of epithelial-to-mesenchymal transition
(EMT) markers. In aim 3, we will determine the role of CC β-catenin in Mdr2 KO mice by its deletion from this
cell type. We will also study the impact of dual deletion of β-γ-catenin in CC. Thus our proposed studies will
comprehensively address the 3 poorly understood processes of epithelial to mesenchymal reprogramming, loss
of cell polarity, and perturbations in cell-cell junctions, in the pathogenesis of CLD.
Terms: <2aR phosphoprotein I><2ar peptide><Address><Adherens Junction><Adhering Junction><Adhesive Junction><Anchoring Junction><Animal Model><Animal Models and Related Studies><Beta Cadherin-Associated Protein><Beta-1 Catenin><Bile><Bile Acid Biosynthesis><Bile Acid Biosynthesis Pathway><Bile Acids><Bile Duct Obstruction><Bile Juice><Bile fluid><Biliary Stasis><Biological><Biology><Bone-Derived Transforming Growth Factor><Byler's disease><Byler's syndrome><CUL-2><Causality><Cell Body><Cell Communication and Signaling><Cell Growth and Maintenance><Cell Junctions><Cell Maintenance><Cell Maturation><Cell Polarity><Cell Signaling><Cells><Characteristics><Childhood><Cholestasis><Chronic><Clinical><Closure by Ligation><Compensation><Defect><Desmoplakin III><Disease><Disease Progression><Disorder><Disparate><Epithelium><Eta-1 protein><Eta-1-Op protein><Etiology><Event><Failure to Thrive><Familial intrahepatic cholestasis><Fatal familial intrahepatic cholestasis syndrome><Fatal intrahepatic cholestasis><Fibrosis><Funding><Genes><Hepatic Cells><Hepatic Parenchymal Cell><Hepatic Transplantation><Hepatocyte><Human><Impairment><Injury><Intercellular Junctions><Intracellular Communication and Signaling><Investigation><Junction Plakoglobin><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Life><Ligation><Liver><Liver Cells><Liver Fibrosis><Liver Grafting><Liver Transplant><LoxP-flanked allele><MTACR1><Medical><Mesenchymal><Mice><Mice Mammals><Milk Growth Factor><Modeling><Modern Man><Murine><Mus><Null Mouse><PRO2286><Pathogenesis><Pathway interactions><Patients><Phenotype><Platelet Transforming Growth Factor><Pre-Clinical Model><Preclinical Models><Process><Progressive intrahepatic cholestasis><RNA Seq><RNA sequencing><RNAseq><Regulation><Role><Sample Size><Signal Transduction><Signal Transduction Systems><Signaling><Site><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Therapeutic><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><WAGR><WIT2><WT1><WT1 Gene Product><WT1 Protein><WT1 gene><WT2><WT2 gene><WT33><Wilms Tumor 1><Wilms Tumor 2 Gene><Wilms tumor suppressor WT1><advanced disease><advanced illness><beta catenin><bile acid anabolism><bile acid biosynthetic process><bile acid formation><bile acid synthesis><bile duct><bile ductule><bile obstruction><bile occlusion><biologic><biological signal transduction><bone sialoprotein 1><bone sialoprotein I><causation><cell type><cellular polarity><cholangiocyte><cholestatic diseases><cholestatic disorder><cholestatic liver disease><cholestatic liver disorder><cholestatic syndromes><clinical relevance><clinically relevant><differential expression><differentially expressed><disease causation><disease model><disease phenotype><disease subgroups><disease subtype><disorder model><disorder subtype><early T-lympocyte activation-1 protein><epithelial to mesenchymal transition><fibrotic liver><floxed><floxed allele><gamma catenin><hepatic body system><hepatic fibrosis><hepatic organ system><human data><human disease><iPS><iPSC><iPSCs><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><injuries><innovate><innovation><innovative><insight><liver transplantation><model of animal><mortality><mouse model><murine model><novel><osteopontin><pathway><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><pediatric><plakoglobin><prevent><preventing><primary sclerosing cholangitis><progressive familial intrahepatic Cholestasis><secreted phosphoprotein 1><sialoprotein 1><social role><transcriptional differences><transcriptome sequencing><transcriptomic sequencing><transcriptomics><β-catenin>