# Targeting the transcriptional co-activators YAP and TAZ with statins to prevent solid organ transplant rejection by HLA donor specific antibodies

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $710,735

## Abstract

PROJECT ABSTRACT
Solid organ transplant recipients exhibiting HLA donor specific antibodies (DSA) are at risk for graft loss due to
chronic antibody-mediated rejection (cAMR) and develop a progressive vascular disease known as transplant
vasculopathy (TV). Although cAMR and TV are highly significant clinical problems across different solid organ
transplants the mechanisms by which DSAs directed against HLA I and HLA II contribute to cAMR and TV are
not yet understood. Novel mechanistic targets and therapeutic approaches to prevent and treat cAMR and TV
are urgently needed. Previously, we demonstrated that DSA-induced ligation of HLA molecules expressed in the
surface of endothelial cells (ECs) induces signaling pathways that regulate survival, proliferation and migration,
all of which are highly relevant to TV. However, the key transcriptional programs stimulated by ligation of HLA
molecules remain to be identified. This gap in understanding hinders effective therapeutic targeting of DSA
effector functions to prevent cAMR and TV. Based on our new results, we posit that the transcriptional co-
activator Yes-Associated Protein (YAP) and its paralog WW-domain-containing Transcriptional co-Activator with
PDZ-binding motif (TAZ), two central effectors of the Hippo pathway, are downstream points of convergence
and integration in the mitogenic and migratory signaling initiated by DSAs in ECs. Although inhibition of the
activity of transcription factors or their co-activators is a challenging strategy, recent evidence suggests a new
avenue to target YAP/TAZ activity via drugs of the statin family. Importantly, epidemiological studies indicate
that statins exert a beneficial effect in clinical transplant populations. Based on substantial preliminary studies,
the central hypothesis of this proposal is that YAP and its paralog TAZ play a crucial role in promoting the
proliferation and migration of ECs in response to DSAs and that the FDA-approved drugs of the statin family
inhibit YAP/TAZ function in these cells. A fundamental translational implication of our hypothesis is that the drugs
of the statin family can be an important element in preventing cAMR by blocking growth-promoting YAP/TAZ
signaling in ECs. We propose to explore this central hypothesis by pursuing three Specific Aims: 1) Determine
the regulation and function of YAP in human ECs stimulated with antibodies directed against HLA I or HLA II:
role of Src kinases. 2) Define the mechanism(s) by which statins inhibit YAP function, proliferation and migration
of ECs stimulated with antibodies directed against HLA I or HLA II. 3) Characterize the impact of statins on YAP
and cAMR in vivo using a novel model of heart graft allograft that develop TV. We propose that the Src/YAP/TAZ
axis plays a critical role in antibody-mediated EC proliferation and that statins inhibit EC proliferation and TV via
YAP/TAZ inhibition. We anticipate that the Src/YAP/TAZ axis will emerge as a novel target in cAMR thus
pr...

## Key facts

- **NIH application ID:** 10890862
- **Project number:** 5R01AI173050-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Robert L Fairchild
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $710,735
- **Award type:** 5
- **Project period:** 2023-07-19 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890862

## Citation

> US National Institutes of Health, RePORTER application 10890862, Targeting the transcriptional co-activators YAP and TAZ with statins to prevent solid organ transplant rejection by HLA donor specific antibodies (5R01AI173050-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10890862. Licensed CC0.

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