# YAP-IRGM1 REGULATES HEPATIC INFLAMMATION IN ORTHOTOPIC LIVER TRANSPLANTATION

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $195,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Hepatic ischemia and reperfusion injury (IRI) remains a common problem in liver transplant, hepatic resection,
and shock. As it often leads to primary graft dysfunction (PGD), late chronic rejection, and contributes to the
shortage of donor organs available for transplantation, liver IRI represents one of the most challenging yet
understudied complications in clinical orthotopic liver transplantation (OLT). As intrinsic YAP expression
negatively correlated with liver function and tissue damage in human OLT, treatment with YAP activator
ameliorated liver IRI by depressing macrophage function and improving hepatocyte protection in a
non-transplant model of hepatic “warm” IRI. Here, the function of distinct YAP signaling pathways is proposed to
study in a clinically relevant mouse model of prolonged hepatic cold ischemia followed by OLT. Hypothesis:
downregulated peri-transplant YAP expression is an important driver of graft injury and development of PGD,
and that such reduced YAP expression in liver graft may be of prognostic and therapeutic significance. Cellular
specific YAP distribution, has prompted to put forth a dissection that YAP signaling at the macrophage (innate
immune) regulates inflammation (pathogenic), autophagic reprogramming (homeostatic) and cytoprotection
(anti-oxidative) during IR-stress in cold-stored murine OLTs. The following three specific aims are proposed:
Aim 1: Determine whether downregulated macrophage YAP expression is a risk factor for developing
PGD in cold-stored murine OLTs? Based on preliminary data, genetically modified mice strain (YAPM-KO) will
be used to evaluate pre-OLT and post-OLT YAP expression on residential and circulation macrophage in relation
to PGD events in a clinically relevant mouse model of extended hepatic cold storage followed by OLT.
Aim 2: Define regulatory mechanisms by which YAP signaling controls immunity-related GTPase family
M member 1 (IRGM1)-dependent macrophage inflammation in IR-stressed OLTs. Hypothesis: YAP
activation modulates macrophage IRGM1 in liver IRI by coupling cyclic GMP-AMP synthase (cGAS) and
interferon regulatory factor 3 (IRF3), which in turn mitigates liver IRI by diminishing innate pro-inflammatory
responses. YAP-mediated IRGM1 deprivation will be screened in IRI-OLTs. Then, a new model of liver IRI in
CD11b-DTR mice in which adoptive transfer of distinctive macrophage populations (after conditional depletion of
native CD11b+ cells) will be utilized to dissect YAP–IRGM1 cross-regulation in hepatic IR-inflammation.
Aim 3: Define molecular mechanisms by which YAP controls IRGM1-dependent macrophage autophagy
in IR-stressed OLTs. Hypothesis: YAP deficiency augments IRGM1-mediated macrophage autophagy and
leads into hepatocellular deterioration in IRI-OLT. YAP–IRGM1 mediated major autophagosomal formation in
governing macrophage M1/M2 balance, and the biological significance and mechanisms of IRGM1-derived
macrophage polarization will be assessed...

## Key facts

- **NIH application ID:** 10350169
- **Project number:** 1R21AI166290-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Haofeng Ji
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $195,000
- **Award type:** 1
- **Project period:** 2022-04-07 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10350169

## Citation

> US National Institutes of Health, RePORTER application 10350169, YAP-IRGM1 REGULATES HEPATIC INFLAMMATION IN ORTHOTOPIC LIVER TRANSPLANTATION (1R21AI166290-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10350169. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*