# Pre-Transplant Monocyte HDAC6 Expression and Risk of Primary Graft Dysfunction in Clinical Lung Transplant Recipients

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $454,430

## Abstract

Project Summary
Primary Graft Dysfunction (PGD) remains a leading cause of early morbidity and mortality in lung transplant (Tx)
recipients. The Lung Transplant Outcomes Group (LTOG) has been studying this problem for the past decade and a newly
NIH-funded LTOG-related project (1U01HL14535-01), headed by Dr. Jason Christie (UPENN), involves long-term follow-
up of adult lung transplant recipients. In preliminary studies, undertaken in collaboration with LTOG, we found that patients
who subsequently developed PGD had significantly elevated pre-Tx levels of HDAC6 mRNA in their peripheral blood
mononuclear cells. We identified CD14+ monocytes as the main source of upregulated HDAC6 in pre-Tx PGD-prone
patients, observed an inflammatory phenotype of those monocytes after stimulation in vitro, and found that HDAC6
targeting significantly decreased cytokine production in an in vivo murine lung model of ischemia/reperfusion injury.
Accordingly, we hypothesize that recipient blood monocytes with upregulated HDAC6 expression pre-lung Tx are
important drivers of graft injury and development of PGD, and that such elevated HDAC6 expression in monocytes may be
of prognostic and therapeutic significance. We propose to test this hypothesis by studying pre-Tx blood samples from
patients enrolled in the parent U01 that began June 15, 2019. Aim 1: Determine if the phenotype of upregulated HDAC6
in monocytes of patients listed for lung Tx is a risk factor for developing PGD? We will expand upon our preliminary
data using a larger sample size to evaluate 1.1) pre-Tx levels of monocyte HDAC6 expression, including mRNA and protein
levels, and co-expression of classical markers of monocyte activation; and 1.2) post-Tx events (PGD with grade) in relation
to the pre-Tx monocyte phenotype. Aim 2: What are the mechanisms by which HDAC6 alters key monocyte
characteristics? We will: 2.1) evaluate cytokine expression (qPCR, flow cytometry, ELISA) by monocytes isolated from
pre-Tx recipients and healthy donors, in relation to their HDAC6 levels; and 2.2) study how high HDAC6 expression
regulates TLR/MyD88 pathway activation. Aim 3: Test whether HDAC6 inhibitor (HDAC6i) therapy can reverse or
diminish the effects of monocyte dysfunction, including ex vivo and in a murine model of PGD. We will: 3.1) test
effects of HDAC6i on monocyte activation, cytokine production and interaction with other immune cells; 3.2) test effects
of one or more novel HDAC6i small molecules (monocyte specific HDAC6i, HDAC6 zinc-finger ubiquitin binding domain
inhibitor and HDAC6i PROTAC); and 3.3) apply HDAC6i in vivo in a recently described new murine model of PGD.
Importantly, our studies will • delineate pathogenic mechanisms of disease; • identify mechanisms or factors that influence
and/or predict response to treatment; and • discover or validate biomarkers of disease development and/or progression.

## Key facts

- **NIH application ID:** 10152233
- **Project number:** 1R01HL154241-01A1
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Wayne William Hancock
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $454,430
- **Award type:** 1
- **Project period:** 2020-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152233

## Citation

> US National Institutes of Health, RePORTER application 10152233, Pre-Transplant Monocyte HDAC6 Expression and Risk of Primary Graft Dysfunction in Clinical Lung Transplant Recipients (1R01HL154241-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10152233. Licensed CC0.

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