# THE RELAXIN RECEPTOR GR/RXFP1 SIGNALING IN LIVER TRANSPLANT ISCHEMIA-REPERFUSION INJURY AND THE INFLAMMATION RESOLUTION

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $390,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Hepatic ischemia/reperfusion injury (IRI), an innate immune-driven inflammation response, is a major obstacle
limiting the success of orthotopic liver transplantation (OLT) in patients with end-stage liver disease and those
with tumors of hepatic origin. Although significant progress has been made in better appreciation of the liver
inflammatory cascade by IR-stress, much less is known about its resolution, which may affect not only the
severity of tissue injury itself but also, more importantly, the long-term outcomes. Recent studies document
striking cytoprotective functions of hrRLX (recombinant human relaxin-2) against IR-stress in mouse OLT models
via hepatocyte glucocorticoid receptor (GR) signaling; while polarizing macrophage activation via Notch1
promoted IRI-OLT resistance. These experimental findings, supported by a clinical evidence of enhanced
GR/Notch1 phenotype needed for IRI resistance in human OLT, prompted to propose that rhRLX may function
as a novel GR agonist and glucocorticoid (GC) mimetic in liver transplantation. Pilot studies also point to anti-
fibrotic functions of the cognate RXFP1 receptor, a GR-independent RLX-2 binding partner. As the conventional
murine OLT model offers a limited translational utility, this project will be dissecting GR – RXFP1 molecular
interplay in mice expressing human RXFP1 gene; as well as testing new concepts of RXFP1-driven hepatic
rejuvenation of discarded human livers during hypothermic machine preservation. A newly discovered divergent
role of GR–RXFP1 signaling axis in the “acute” and “resolution” phase of IRI-OLT inflammation, has prompted
to put forth a novel and heretofore untested overall hypothesis, that: 1/ pharmacological rhRLX-induced GR
enhancement will rescue OLT from acute IR-insult; while 2/ harnessing GR-independent rhRLX signaling via its
cognate receptor, RXFP1, will promote homeostatic/anti-fibrotic functions in the inflammation resolution phase.
Two interlocked aims explore this hypothesis:
Aim 1: Delineate molecular mechanisms of rhRLX – GR hepatocellular protection in OLT (acute IRI-inflammation
phase). Aim 1.1: Test hypothesis that hepatocellular Keap1-dependent Nrf2 signaling is indispensable for rhRLX
– GR axis to prevent DAMPs release and innate inflammation in cold-stored donor livers. Aim 1.2: Test
hypothesis that SIRT1 enhances GR-induced hepatocyte regenerative functions/autophagy in IR-stressed OLT.
Aim 2. Delineate molecular mechanisms of Notch1 / RXFP1 anti-fibrotic functions in OLT (IRI-inflammation
“resolution” phase). Aim 2.1: Test hypothesis that Notch1 (macrophage) – RXFP1 (T cell) cross-regulation is
essential in the resolution of IRI – OLT inflammation. Aim 2.2: Test hypothesis that the activation of human RLX
receptor exerts anti-fibrotic functions in the resolution of IRI-OLT inflammation in humanized RXFP1 “knockin”
mouse system. Aim 2.3: Test hypothesis that activation of RXFP1 receptor during hypothermic machine
preservat...

## Key facts

- **NIH application ID:** 10685284
- **Project number:** 5R01AI155856-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Jerzy W Kupiec-Weglinski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2020-09-22 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10685284

## Citation

> US National Institutes of Health, RePORTER application 10685284, THE RELAXIN RECEPTOR GR/RXFP1 SIGNALING IN LIVER TRANSPLANT ISCHEMIA-REPERFUSION INJURY AND THE INFLAMMATION RESOLUTION (5R01AI155856-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10685284. Licensed CC0.

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