# Nur77 Suppresses Sepsis-Induced Endothelial Dysfunction

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $296,400

## Abstract

Project Summary
Endothelial dysfunction induced by barrier dysfunction and hyper-coagulation is one of the major pathological
features of sepsis for which no effective treatment exists. Therefore, identifying novel molecular mechanisms
regulating the cross-talk of vascular barrier function and coagulation during sepsis is of great scientific and
therapeutic interest. The current proposal arises from our discovery that orphan nuclear receptor Nur77 is a
critical determinant controlling vascular inflammation, hyperpermeability, and microvascular thrombosis in
response to septic injury. Our data show that Nur77 can simultaneously suppress NF-kB activation while
exerting potent anti-thrombotic effects by increasing thrombomodulin (TM) expression and upregulating levels
of activated protein C (APC) in vascular endothelial cells (ECs). The protective effects of Nur77 are dependent
on early up-regulation in the vascular endothelium and that failure to increase its expression immediately after
injury leads to a dramatic increase in vascular permeability and inflammation. Further, we show that the barrier
protective effects of Nur77 appear to be mediated through upregulation of sphingosine kinase 1 (SphK1), as
SphK1 and its downstream product sphingosine-1-shosphate (S1P), are substantially reduced in Nur77-
deficient ECs exposed to lipopolysaccharide (LPS). Based on the collective strength of these data, we
hypothesize that Nur77 serves as an essential brake to limit the severity of endothelial dysfunction in sepsis,
and targeted activation of Nur77 can effectively treat sepsis by its concomitant anti-inflammatory, anti-
hyperpermeability, and anti-thrombotic activities. To test this hypothesis, 3 specific aims are proposed. Aim 1
will establish the endothelial specific role of Nur77 in maintaining vascular homeostasis in sepsis by assessing
whether mice with targeted deletion of Nur77 in endothelium are more susceptible to septic injury as a result of
increased vascular leakage, inflammation, and prothrombotic activities. Aim 2 will delineate the molecular
mechanisms by which Nur77 improves barrier function in endothelial cells. The regulation of the SphK1/S1P
pathway by Nur77 and the functional importance of the Nur77/S1P axis in the Nur77-mediated stabilization of
endothelial barrier function will be determined. Aim 3 will establish the therapeutic capacity of Nur77 activators
in the treatment of sepsis. Our study will elucidate a critical mechanism underlying the regulation of endothelial
barrier function and inflammation in sepsis and establish that this mechanism can be targeted to treat sepsis.
The predicted utility and feasibility of such targeting in humans favors the translational potential and ultimate
impact of the proposed studies.

## Key facts

- **NIH application ID:** 9879747
- **Project number:** 5R01GM123047-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Jianxin Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $296,400
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879747

## Citation

> US National Institutes of Health, RePORTER application 9879747, Nur77 Suppresses Sepsis-Induced Endothelial Dysfunction (5R01GM123047-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9879747. Licensed CC0.

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