# Blocking hepatocyte senescence as a novel therapeutic strategy for chronic liver diseases

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $608,113

## Abstract

Summary:
There is growing evidence implicating that cellular senescence is involved in the progression of chronic liver
diseases (CLD). However, the mechanisms underpinning cellular senescence-mediated progression of CLD
remain unclear. We have recently reported an important role of the activin A/p15INK4b axis in inducing
hepatocyte (HC) senescence. Further suggesting a role of the activin A/p15INK4b axis in inducing HC
senescence in CLD, because our preliminary data from rat models of liver cirrhosis revealed increased
activin A and p15INK4b expression in cirrhotic liver tissue regions, which correlated with increased hepatic
SA-β-gal activity. We also found that elevated p15INK4b expression in the livers of mice treated with CCl4 and
observed that activin A inhibition markedly reduced CCl4-induced hepatic injury. Increased levels of activin
A are also reported in several human CLDs, and our preliminary data demonstrate increased activin A
expression in the livers of cirrhosis patients. Based on this evidence, we hypothesized that activin A
contributes to the pathogenesis of CLDs by driving p15INK4b-mediated induction of HC senescence.
Senescence-associated secretory phenotype (SASP) factors produced by senescent HCs promote
inflammation and fibrosis, resulting in CLD progression. We will test our hypothesis using our
established rat HC transplantation model and rodent models of CLD according to the following integrated
Specific Aims. In Aim 1, we will use our HC-transplantation model to precisely demarcate senescent and
neighboring cells, followed by isolation of both cell populations using laser-capture microdissection (LCM).
Comparative analyses of these foci and their surrounding regions will reveal paracrine signals from
senescent HCs and their phenotypic effects on neighboring HCs. Aim 2 will investigate the effect of activin
A/p15INK4b-induced HC senescence in both rat and mouse models of CLD. Studies in the mouse model will
also include a comprehensive phenotypic and functional analysis of hepatic immune cell infiltrates to
determine the impact of HC senescence on immune cells. We will also evaluate hepatic expression of
activin A and p15INK4b in cirrhotic patients by confocal microscopy to determine the clinical relevance of the
activin A/p15INK4b axis. Lastly, in Aim 3, we will investigate the therapeutic benefit of targeting senescence in
CLDs. This application leverages our combined expertise in liver transplantation models (Oertel, MPI),
animal models of liver diseases (Oertel/Raeman, MPIs), immunology (Raeman), and senescence (Oertel),
as well as extensive experience in hepato-pathology and RNA-seq analyses (Locker, Co-I) and
lentiviral/AAV expression systems (Bell, Co-I), to investigate the mechanisms underpinning HC senescence
and the role of senescent HCs and their detrimental effects on neighboring cells in the pathogenesis of
CLD. The results of our investigations will lead to identification of therapeutic strategies to preven...

## Key facts

- **NIH application ID:** 10339654
- **Project number:** 1R01DK130949-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Michael Oertel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $608,113
- **Award type:** 1
- **Project period:** 2021-09-30 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339654

## Citation

> US National Institutes of Health, RePORTER application 10339654, Blocking hepatocyte senescence as a novel therapeutic strategy for chronic liver diseases (1R01DK130949-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10339654. Licensed CC0.

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