# Mechanisms of MKP-1-mediated MAP kinase Signaling in Liver injury

> **NIH NIH P01** · YALE UNIVERSITY · 2020 · $309,875

## Abstract

PROJECT SUMMARY/ABSTRACT 
The balance between hepatocyte life and death is regulated through multiple signaling pathways. Activation of 
the mitogen-activated protein kinase (MAPK) pathway represents an important and fundamental mechanism 
through which hepatocyte function and longevity is achieved. Although propagation of the stress-responsive 
MAPKs is critical for the promotion of both signals that confer hepatocyte life and death much less is 
understood about the signals that inactivate the MAPKs in the liver and how these signals participate in the 
progression of liver disease. The broad goal of this project is to define the role of the MAP kinase 
phosphatase-1 (MKP-1) in the management of liver injury. Liver injury is often one of the early precipitating 
events in the progression towards liver disaease that is often facilitated by chronic inflammation. We have 
found that whole body MKP-1-deficient mice exhibit resistance to the development of non-alcoholic 
steatohepatitis (NASH) and in response to injury are impaired in their ability to regenerate liver. We will test the 
hypothesis that hepatic MKP-1 serves as an essential regulator of stress-responsive MAPK signaling in the 
control of liver injury. In aim 1, we will use liver-specific MKP-1 knock-out mice to determine the contribution of 
MKP-1 in the liver and macrophage in the progression of NASH. Aim 2 will focus on the observation that 
hepatic MKP-1 is required for liver regeneration. We will will elucidate the mechanisms through which MKP-1 
regulates liver regeneration by examining how it serves to control the expression of the hepatokine, interleukin 
6. In aim 3, phosphoproteomic approaches will be employed to identify MKP-1-regulated MAPK substrates 
involved in liver stress and repair. Hepatic MKP-1-regulated MAPK substrates will be characterized and tested 
for their roles in liver stress-responsive signaling. These studies will be integrated with the analysis of MKP-1 
and its identified regulatory MAPK substrates in various human settings of liver disease. The succesful 
implementation of these studies will provide new insight in to the mechanisms the liver invokes in response to 
injury and as such may reveal new therapeutic avenues for the treatment of liver disease.

## Key facts

- **NIH application ID:** 9931210
- **Project number:** 5P01DK057751-20
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Anton M Bennett
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $309,875
- **Award type:** 5
- **Project period:** — → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931210

## Citation

> US National Institutes of Health, RePORTER application 9931210, Mechanisms of MKP-1-mediated MAP kinase Signaling in Liver injury (5P01DK057751-20). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9931210. Licensed CC0.

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