# Pathobiology of Hepatic Epithelia

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2022 · $357,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Our GOALS are to continue to clarify the pathogenesis of polycystic liver disease (PLD) and develop
effective therapies. PLD is a genetic ciliopathy for which there are no regulatory approved drugs. We reported
that PLD cholangiocytes (PLDC) have increased cAMP, accelerated autophagy, and structurally and
functionally malformed cilia. However, it remains unclear what mechanisms are involved, how they contribute
to hepatic cystogenesis, or if they represent new therapeutic targets. Based on recent published observations
and our preliminary data, our OVERALL OBJECTIVES are to explore the mechanistic relations between
autophagy of ciliogenic proteins (i.e., proteins involved in cilia maintenance), pro-cystogenic signaling and
hepatic cystogenesis. Our preliminary data show: i) autophagy, cilia, and cAMP signaling are the most altered
biological processes in human PLDC vs. normal cholangiocytes (NHC) as assessed by RNAseq and gene
enrichment analysis; ii) ciliogenic proteins are diminished in PLDC cilia but increased in autophagosomes
isolated from PLDC; iii) in PLDC, HDAC6 is increased and ubiquitinates ciliogenic proteins; iv) in PLDC, the G-
protein coupled bile acid receptor, TGR5, is depleted in cilia due to autophagic degradation of ciliogenic
proteins that normally target TGR5 to cilia, is overexpressed at the apical membrane and its activation further
increases cAMP; and v) genetic elimination of the ciliogenic protein, Kif3A, from cholangiocytes in mice leads
to malformed TGR5-depleted cilia, TGR5 overexpression at the apical membrane, and hepatic cystogenesis.
Thus, our data support the CENTRAL HYPOTHESIS that in PLD, HDAC6-dependent autophagy of
ciliogenic proteins disrupts ciliogenesis resulting in malformed cholangiocyte cilia, ciliary depletion of
TGR5, enhanced pro-cystogenic signaling and hepatic cyst growth. We will test this hypothesis by using
biochemical, molecular and microscopic techniques, cultured and freshly isolated human and rodent normal
and PLD cholangiocytes, unique animal models, and human tissue. Our proposal has three integrated
SPECIFIC AIMS. First, we test the hypothesis that autophagy-mediated, HDAC6-dependent depletion of
ciliogenic proteins disrupts ciliogenesis in PLDC resulting in malformed cilia. Second, we test the hypothesis
that autophagy of ciliogenic proteins depletes cholangiocyte cilia of TGR5 and enhances pro-cystogenic
signaling and cyst growth. Third, we test the hypothesis that pharmacologic interventions that target
cholangiocyte autophagy and ciliogenesis (ciliotherapy) inhibit cystogenesis in vitro and in animal models of
PLD. These innovative experiments will: i) clarify how autophagy of ciliogenic proteins leads to ciliary
malformations; ii) address how HDAC6-mediated autophagy of ciliogenic proteins disrupts ciliary targeting of
TGR5, thereby increasing pro-cystogenic cAMP signaling and cyst growth; and iii) explore how pharmacologic
manipulations of autophagy and cili...

## Key facts

- **NIH application ID:** 10376789
- **Project number:** 5R01DK024031-42
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Nicholas F. LaRusso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $357,750
- **Award type:** 5
- **Project period:** 1978-12-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376789

## Citation

> US National Institutes of Health, RePORTER application 10376789, Pathobiology of Hepatic Epithelia (5R01DK024031-42). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10376789. Licensed CC0.

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