# Beta-catenin-driven hepatobiliary reprogramming as a therapeutic modality for cholangiopathies

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $400,869

## Abstract

Cholangiopathies are chronic, progressive diseases of the biliary tree, and can be either acquired or genetic. Regardless of
etiology, cholangiopathies share common pathologic mechanisms, including inflammation, aberrant ductular proliferation,
fibrosis, ductopenia, and cholestasis, which can over time result in tumorigenesis, cirrhosis, or liver failure. Despite recent
advances in our understanding and diagnosis of these diseases, there are no proven therapeutic treatments for the majority
of cholangiopathies. Thus, mechanistic-based studies that emphasize therapeutic development are desperately needed.
Previous work has identified the Wnt/β-catenin signaling pathway as a modulatable target in mouse models of biliary
injury such as 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Overexpression of a mutated non-degradable form
of β-catenin in transgenic (TG) mice subjected to long-term DDC results in a significant reduction in serum alkaline
phosphatase, a common prognostic marker for biliary injury, and a concurrent increase in bile flow. Notably, this
improvement was associated with widespread expression of biliary marker A6 in the hepatocytes (HC) of these TG mice.
Further analysis revealed that TG had increased expression of biliary markers in HC as early as 1 month after DDC.
During biliary injury, HC are known to alter their phenotype and acquire cholangiocyte (CC)-like features, a process
known as cellular reprogramming. HC reprogramming may contribute to biliary repair by modifying bile to reduce
toxicity, serving as a source of de novo CC to repair the biliary epithelium, or creating new channels to facilitate bile flow.
Thus, the overarching hypothesis of the proposal is that activation of Wnt/β-catenin signaling in HC during cholestasis
will induce reprogramming to a CC-like phenotype, and that this process will aid in restoring bile flow and reducing the
severity of cholestatic liver disease. In aim 1, we will unambiguously determine if β-catenin-overexpressing HC fully
differentiate into functional CC or maintain an intermediate phenotype during cholestasis by isolating permanently labeled
HC and their progeny and analyzing them through phenotypic characterization, functional tests, and transcriptomic
analysis. In aim 2, we will characterize the mechanism by which Wnt/β-catenin activates a biliary phenotype in HC by
using unbiased methods to identify the transcription factors downstream of β-catenin in cholestasis, as well as evaluating
the contribution of Yap signaling as a potential downstream effector of β-catenin using an in vivo two-gene reporter
system. In aim 3, we will determine whether activating β-catenin in HC will enhance transdifferentiation into fully-
functional CC in the absence of a functional biliary system. First, we will determine the effect of inhibiting or
overexpressing β-catenin on the formation of biliary structures in vitro (HC-derived organoid cultures). Next, we will
exogenously activate β-catenin us...

## Key facts

- **NIH application ID:** 10180952
- **Project number:** 5R01DK119435-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kari N Nejak-Bowen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $400,869
- **Award type:** 5
- **Project period:** 2019-09-20 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180952

## Citation

> US National Institutes of Health, RePORTER application 10180952, Beta-catenin-driven hepatobiliary reprogramming as a therapeutic modality for cholangiopathies (5R01DK119435-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10180952. Licensed CC0.

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