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Principal Investigator: Donghun Shin
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $496,215
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
ABSTRACT
Biliary epithelial cells (BECs; also called as cholangiocytes) that line the hepatic biliary tree control bile
composition and flow. Injury to the BECs leads to cholestasis, which can progress to fibrosis, cirrhosis and liver
failure. Cholestatic liver diseases are associated with high morbidity and mortality; however, few effective
therapies are available. In fact, liver transplantation is the only life-extending treatment for end-stage cholestatic
liver diseases, but the shortage of donor livers makes this therapy extremely limited. In the injured liver with
biliary damage, hepatocytes (HCs) can contribute to BECs to recover from the loss of BECs. Recent studies in
mice have shown that HC-derived BECs contribute to the intrahepatic bile ducts, thereby restoring appropriate
bile flow. Patients with biliary obstruction or cholangiopathies also exhibit biliary marker expression in HCs,
suggesting their reprogramming into BECs. Thus, augmenting innate HC-to-BEC reprogramming in cholestatic
liver diseases is an attractive therapeutic alternative to ameliorate cholestasis and subsequent cirrhosis. To
develop such a therapy, it is crucial to better understand the molecular mechanisms underlying HC-to-BEC
reprogramming. Furthermore, identifying small molecules that can augment the reprogramming should provide
promising therapeutic drugs for patients with cholestatic liver diseases. Our long-term goal is to completely
delineate the molecular mechanisms underlying HC-to-BEC reprogramming. As a first step in pursuit of that goal,
the objective of this proposal is to determine the cellular and molecular characteristics of HC-to-BEC
reprogramming-driven biliary regeneration in our two innovative zebrafish models and to elucidate how histone
deacetylase 1 (hdac1) regulates HC-to-BEC reprogramming. Based on our preliminary data obtained from
pharmacological and genetic studies, we hypothesize that Hdac1 inhibition promotes HC-to-BEC reprogramming
by derepressing the Notch receptor gene notch2 and the signal transducer and activator of transcription 3 gene
(stat3). We will test this hypothesis and accomplish the objective of this application by (1) elucidating the entire
process of HC-to-BEC reprogramming-driven biliary regeneration in the two zebrafish models, in which complete
absence of BECs is achieved and subsequently HCs convert to BECs. (Aim 1), (2) determining the effects of
Hdac1 inhibition on HC-to-BEC reprogramming in both zebrafish and mice (Aim 2), and (3) elucidating the
molecular mechanisms by which Hdac1 inhibition promotes the reprogramming (Aim 3). The successful
accomplishment of the proposed research will not only provide novel molecular mechanisms underlying HC-to-
BEC reprogramming but also suggest HDAC1/2 inhibitors as promising therapeutic drugs to promote the
reprogramming in patients with cholestatic liver diseases.
Terms: <APRF protein><Acute-Phase Response Factor><Beta Cadherin-Associated Protein><Beta-1 Catenin><Bile><Bile Duct Obstruction><Bile Juice><Bile Tract><Bile fluid><Biliary><Biliary Stasis><Biliary System><Biliary Tree><Brachydanio rerio><CUL-2><Cell Communication and Signaling><Cell Reprogramming><Cell Signaling><Cell model><Cellular model><Characteristics><Chemicals><Cholestasis><Cirrhosis><Danio rerio><Data><Drugs><E1A Binding Protein p300><EP300><EP300 gene><Epithelial Cells><Exhibits><Fibrosis><Gene Action Regulation><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Genes><Genetic><Genetic study><Goals><HD1><HDAC1><HDAC1 gene><Hepatic><Hepatic Cells><Hepatic Disorder><Hepatic Failure><Hepatic Parenchymal Cell><Hepatic Transplantation><Hepatocyte><Histone Acetylation><Histone Deacetylase 1><IL6-response factor><Image><Injury><Injury to Liver><Intracellular Communication and Signaling><Intrahepatic bile duct><KAT3B><LIF-response factor><Life><Liver><Liver Cells><Liver Failure><Liver Grafting><Liver Regeneration><Liver Transplant><Liver diseases><MS-275><Mediating><Medication><Mice><Mice Mammals><Modeling><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><Natural regeneration><Obstruction><PRO2286><Pathway interactions><Patients><Pharmaceutical Preparations><Pharmacological Study><Pharmacology Study><Phenocopy><Process><RPD3-Like 1><RPD3L1><Receptor Gene><Reduced Potassium Dependency 3, Yeast, Homolog-Like 1><Regeneration><Research><Role><Signal Transducer and Activator of Transcription 3><Signal Transduction><Signal Transduction Systems><Signaling><Stat3 protein><Testing><Therapeutic><Zebra Danio><Zebra Fish><Zebrafish><beta catenin><bile obstruction><bile occlusion><biliary tract><biological signal transduction><cellular reprogramming><cholangiocyte><cholestatic diseases><cholestatic disorder><cholestatic liver disease><cholestatic liver disorder><cholestatic syndromes><cirrhotic><derepression><drug/agent><effective therapy><effective treatment><end stage liver disease><end stage liver failure><gain of function><hepatic body system><hepatic damage><hepatic disease><hepatic injury><hepatic organ system><hepatopathy><histone acetyltransferase p300><imaging><inhibitor><injuries><innovate><innovation><innovative><insight><liver damage><liver disorder><liver injury><liver transplantation><loss of function><mortality><mutant><notch><notch protein><notch receptors><novel><p300><pathway><pharmacologic><regenerate><small molecule><social role><tool><transdifferentiation><β-catenin>