# Regulation of thrombin-induced p38 MAPK pro-inflammatory signaling by deubiquitinases

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $38,890

## Abstract

PROJECT SUMMARY / ABSTRACT
Cardiovascular disease (CVD) is a leading cause of deaths in the United States, however the underlying
inflammatory pathways that contribute to CVD are poorly understood. Endothelial dysfunction is a hallmark of
CVD and induced by various inflammatory mediators, many of which signal through G-protein coupled receptor
(GPCRs). Thrombin, an inflammatory mediator, is generated in response to vascular injury and disrupts
endothelial barrier integrity and promotes vascular leakage, a hallmark of inflammation. Thrombin activates
endothelial protease-activated receptor-1 (PAR1) to disrupt endothelial barrier through the RhoA/myosin light
chain (MLC) pathway. However, thrombin/PAR1-stimulated p38 mitogen-activated protein kinase (MAPK)
signaling also promotes barrier permeability through a pathway that does not integrate with the RhoA/MLC
signaling, suggesting that p38 acts through an uncharacterized pathway to promote inflammatory responses in
endothelial cells. Our previous work showed that thrombin-activated PAR1 ubiquitination drives the recruitment
of TAB2-TAB1 protein complexes on endosomes to trigger non-canonical p38 activation and endothelial barrier
disruption. The mechanisms that regulate PAR1 ubiquitination/de-ubiquitination are not known. This proposal
aims to understand the molecular processes that regulate PAR1-ubiquitin-driven p38 signaling and most
importantly its impact on endothelial barrier integrity. The central hypothesis is that de-ubiquitination of PAR1
leads to termination of p38-mediated pro-inflammatory signaling and will be tested with two specific aims: 1) To
delineate the function of PAR1-specific deubiquitinases (DUBs) enzymes in the regulation of ubiquitin-driven p38
MAPK inflammatory signaling and 2) To study the functional impact of ubiquitination / de-ubiquitination of PAR1
on endothelial barrier permeability. Using advanced biochemical, microscopic and genome-wide RNAi screening
methods, the proposed research plan will allow for the first time to investigate molecular determinants that
regulate the dynamics of PAR1-ubiquitination and the impact on endothelial proinflammatory responses in vitro
using human endothelial cells and in vivo using mice. The contribution of this work is expected to be significant
as this study will reveal new information regarding the function of PAR1 ubiquitination in driving non-canonical
endosomal p38 MAPK signaling in endothelial barrier disruption, a hallmark of inflammation and will further
reveal a new signaling pathway that controls endothelial barrier function, which will provide an opportunity for
the development new strategies for the treatment of inflammatory responses associated with CVD.

## Key facts

- **NIH application ID:** 10465877
- **Project number:** 1F31HL158213-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Norton Cheng
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,890
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465877

## Citation

> US National Institutes of Health, RePORTER application 10465877, Regulation of thrombin-induced p38 MAPK pro-inflammatory signaling by deubiquitinases (1F31HL158213-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10465877. Licensed CC0.

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