# DAMPs and Their Receptors Link Hepatocyte Death to HSC Activation and Liver Fibrosis

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $519,971

## Abstract

Chronic liver disease (CLD) is the 12th leading cause of mortality in the US and causes ≈2 million deaths/year
world-wide, making it a major health problem. Liver fibrosis contributes to the majority of clinical complications
of CLD and is further on the rise due to the global epidemic of obesity and NASH. Despite identification of key
pathways that promote liver fibrosis such as TGFb and PDGF, there is still not a single approved anti-fibrogenic
drug for patients with liver fibrosis. On a mechanistic level, hepatocellular death is a key driver of liver disease
progression, with a 6-fold higher risk for the development of cirrhosis in patients with great than two-fold
increased ALT levels. Likewise, genetic induction of hepatocellular death in mice is sufficient to trigger the
progression to fibrosis. However, mechanisms by which cell death promotes fibrosis remain poorly understood
and therapeutically unexploited. Here, we hypothesize that damage-associated molecular patterns (DAMPs) and
their receptors may provide a direct link between hepatocyte death and fibrogenesis in the liver. Such a
DAMP/DAMP receptor system would endow hepatic stellate cells (HSC), the primary fibrogenic cell type in the
liver, with the ability to sense liver injury via hepatocyte-released DAMPs, resulting in HSC activation and
fibrogenesis as tailored response to hepatocellular injury. Based on whole genome screens, in which we
identified several HSC-enriched candidate DAMP receptors, and subsequent functional in vitro and in vivo
assays, our proposal will focus on P2RY14 and its ligands UDP-glucose, UDP-galactose and UDP-glucuronic
acid as the candidate profibrogenic DAMP/DAMP receptor system in the liver. In Aim 1, we will investigate (i)
which modes of cell death trigger activation of this DAMP/DAMP receptor system; (ii) the mechanisms by which
P2RY14 and its ligands affect HSC activation, proliferation and migration; and (iii) confirm human relevance by
determining P2YR14 expression and P2YR14 ligands in patients and by studying P2RY14-mediated activation
of human HSC. In Aim 2, we will determine the contribution of P2RY14 to liver fibrosis with a particular focus on
NASH, using HSC-specific P2RY14 deletion strategies as well as pharmacologic inhibition of P2RY14 to
establish P2RY14 as potential target for antifibrogenic therapies. Together, the proposed studies will establish
the new paradigm that a specific DAMP-DAMP receptor-ligand pair with cell-specific expression patterns links
hepatocyte death to HSC activation and liver fibrosis, and that it may provide a novel therapeutic target for liver
fibrosis.
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## Key facts

- **NIH application ID:** 10224799
- **Project number:** 5R01DK124104-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Robert F. Schwabe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $519,971
- **Award type:** 5
- **Project period:** 2019-09-20 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224799

## Citation

> US National Institutes of Health, RePORTER application 10224799, DAMPs and Their Receptors Link Hepatocyte Death to HSC Activation and Liver Fibrosis (5R01DK124104-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10224799. Licensed CC0.

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