# EphB2 receptor tyrosine kinase in liver fibrosis

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $190,625

## Abstract

The work proposed in this application identifies a novel family of molecules, the Eph receptors (Erythropoietin
producing hepatocellular) and their Ephrin ligands, that could be targeted to prevent or reverse the
progression of liver fibrogenesis. Despite research progress made in understanding the molecular mechanisms
driving the progression of hepatic fibrogenesis, FDA-approved treatments are still severely limited or in some
cases restricted to the removal of the etiologic agent. A feature of liver fibrosis is the excessive deposition of
extracellular matrix components by activated hepatic stellate cells (HSCs) a process driven by inflammation
and recruitment of immune cells at the site of injury. These immune cells provide the pro-
inflammatory/fibrogenic microenvironment critical for the transdifferentiation of quiescent HSCs into fibrogenic
myofibroblasts.
The molecular basis of liver fibrosis is incompletely understood. Ligation of cell–bound Eph receptors to
membrane-tethered ephrin ligands initiates a bi-directional signaling cascade affecting diverse biological
processes relevant to fibrogenesis including cellular remodelling, angiogenesis, migration/proliferation and
epithelial-to-mesenchymal-transition (EMT). The long-term goal of this project is to develop a therapy based
on targeting the receptor tyrosine kinase (RTK) EphB2 for the treatment of liver fibrosis/cirrhosis. Using
mouse models of liver fibrosis the objective of this exploratory project is to demonstrate that in the liver,
EphB2/ ephrin-B signaling is critical for the transdifferentiation of quiescent HSCs into fibrogenic
myofibroblasts during fibrogenesis. The central hypothesis being tested in this proposal is that upon chronic
liver injury, HSCs upregulate EphB2 and when bound to Ephrin-B ligands expressed on various cells of the
liver microenvironment, activated EphB2-expressing HSCs initiate a differentiation process leading to their
transformation into fibrogenic myofibroblasts. This hypothesis has been formulated from our preliminary data
showing that EphB2 is highly upregulated in both the fibrotic livers of mice and in human liver cirrhosis. HSCs
express EphB2 and its deficiency in mice attenuates liver fibrosis in both infectious and non-infectious
models. Guided by strong preliminary data the central hypothesis will be tested by pursuing 3 specific aims:
 Aim 1: Demonstrate that signaling via the cytoplasmic domain of EphB2 is required for liver
fibrogenesis.
 Aim 2: Demonstrate that TGF-β1 regulates EphB2/Ephrin-Bs expression on HSCs.
 Aim 3: Determine whether therapeutic targeting EphB2 will mitigate liver fibrogenesis.
To our knowledge this highly innovative and novel exploratory work is the first to investigate the role of a
member of the Eph receptors in non-pathogen driven liver fibrogenesis. The proposed research is significant
because it has great translational potential to provide a new therapeutic target (EphB2) for future clinical
studies against liv...

## Key facts

- **NIH application ID:** 9963266
- **Project number:** 5R21DK115991-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Patrice Mimche
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $190,625
- **Award type:** 5
- **Project period:** 2018-08-17 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963266

## Citation

> US National Institutes of Health, RePORTER application 9963266, EphB2 receptor tyrosine kinase in liver fibrosis (5R21DK115991-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9963266. Licensed CC0.

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