# HuR/HIF – SIRT1 Signaling Axis in Liver Transplant Rejuvenation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $461,163

## Abstract

ABSTRACT
Orthotopic liver transplantation (OLT) is the gold standard of care in patients with end-stage liver disease and
those with tumors of hepatic origin. However, the scarcity of donor organs prompted the use of extended criteria
“marginal” livers, which are particularly susceptible to ischemia-reperfusion injury (IRI), which predispose to
acute/chronic rejection, and may require re-transplantation. We have introduced the concept of organ
“rejuvenation”, i.e., conversion of the donor liver from the state of IRI-hypersensitivity to the homeostatic state of
IRI-resistance. We have also proposed that SIRT1 deacetylase serves as a rheostat linking IR-stress with liver
rejuvenation in both, mouse and human OLT. We have recently identified new regulators of hepatic resistance
against warm vs. cold ischemia stress responses, i.e., Human Antigen R (HuR) and Hypoxia-Inducible Factor
(HIF-1α). We have also discovered Ikaros (IKZF1), acts as a macrophage activation marker and exacerbates
liver IRI. Importantly, we also found that preserved hepatocellular function/improved clinical outcomes in human
OLT patients were associated with increased HuR/HIF-1α but depressed Ikaros levels in the liver biopsy
samples. We hypothesize that crosstalk between hepatocyte HuR / HIF-1α and macrophage Ikaros provides a
new means to regulate the adaptation of donor livers to IR-stress and reperfusion-mediated hepatic damage.
Specific Aim 1: Determine mechanisms of hepatocyte HuR / HIF-1α crosstalk with SIRT1 in IRI-OLT.
Hypothesis: Hepatocyte SIRT1 activation, controlled by distinct hypoxia/reoxygenation (H/R) requirements for
HuR (warm H/R) vs. HIF-1α (cold H/R), provide new means to regulate adaptation of donor livers to IR-stress.
1.1: SIRT1 function is dependent on HuR signaling for anti-inflammatory responses in oxidative stress. 1.2:
HuR/HIF-1α signaling in a mouse model of hepatic ischemia is temperature stress-dependent. 1.3: HIF-1α
controls cold-induced IRI-OLT. 1.4: HuR controls warm-induced IRI-OLT.
Specific Aim 2: Delineate mechanisms of macrophage Ikaros crosstalk with SIRT1 in IRI-OLT.
Hypothesis: Macrophage Ikaros signaling exacerbates IRI-OLT by repressing SIRT1 transcription and M2
macrophage polarization. 2.1: Ikaros-SIRT1 myeloid axis influences hepatic HuR/HIF1α hypoxia sensing circuit
in IRI-OLT. 2.2: Macrophage Ikaros signaling depends on SIRT1 transcription for M2 polarization.
Specific Aim 3: Define mechanism of human liver rejuvenation under hypothermic machine preservation.
Hypothesis: Manipulation of HIF-1α / SIRT1 axis during ex-vivo HMP improves hepatocellular function to
rejuvenate human livers declined for transplantation due to preexisting poor quality. 3.1: Pharmacological
stabilizer of HIF-1α protein synergizes with SIRT1 to improve human liver function. 3.2: Preconditioning with
PHD-inhibitor, which activates/stabilizes HIF-1α, synergizes with enhanced SIRT1 signaling to ameliorate
inflammation, promote cytoprotection, and rejuvenate hu...

## Key facts

- **NIH application ID:** 10211459
- **Project number:** 2R01DK062357-16
- **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:** 2021
- **Award amount:** $461,163
- **Award type:** 2
- **Project period:** 2003-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10211459

## Citation

> US National Institutes of Health, RePORTER application 10211459, HuR/HIF – SIRT1 Signaling Axis in Liver Transplant Rejuvenation (2R01DK062357-16). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10211459. Licensed CC0.

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