# Role of ADAM17 in MDSC-Mediated Development of Pulmonary Hypertension

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $381,250

## Abstract

PROJECT SUMMARY
While it is known that a reduction in leukocyte recruitment through inhibition of chemokine receptor CXCR2
attenuates development of pulmonary hypertension (PH) in murine models of disease – and that activated pep-
tidase ADAM17 levels are associated with improved vascular remodeling – the role of ADAM17 in CXCR2-
mediated myeloid cell trafficking leading to the development of PH is unknown. There is an urgent need to close
this gap in knowledge because, until accomplished, immunotherapeutic modulation of myeloid-derived suppres-
sor cell (MDSC) contribution to the development of pulmonary vascular disease will remain beyond reach. The
overall objective of the proposed experiments is to define the contribution of ADAM17 in polymorphonuclear-
MDSC (PMN-MDSC) recruitment within the lung vasculature. The central hypothesis is that reduced ADAM17
expression and activity by PMN-MDSC is necessary for recruitment of these cells to the pulmonary vasculature
leading to PH. The scientific premise for this hypothesis has been formulated on the basis of preliminary data
demonstrating that PMN-MDSC expressing CXCR2 are necessary for development of PH in animal models of
disease, and that this circulating cell population is present to a higher degree in whole blood of IPF patients.
Additionally, ADAM17 levels inversely correlate with CXCR2 expression, and are associated with development
of severe PH. The rationale for the proposed research is that, upon completion of the studies it will be possible
to apply current MDSC-targeted therapies to disease prevention and treatment, as well as inform potential harms
in the use of ADAM17-targeted treatments for other diseases. The central hypothesis will be tested by pursuing
the following specific aims: 1) test the hypothesis that ADAM17 expression and functional activity is differentially
regulated in PMN-MDSC isolated from patients with PH and idiopathic pulmonary fibrosis (IPF), and 2) test the
hypothesis that ADAM17 expression by PMN-MDSC protects against pathologic pulmonary vascular remodel-
ing. In the first aim, peripheral blood samples from patients with IPF with and without PH will be collected, in
order to define a MDSC profile in patients with disease and controls, based upon flow cytometric analysis for
MDSC sub-types. Cell populations will then be characterized for allelic discrimination of an identified biomarker
candidate, in addition to assessment of ADAM17 functional activity, including shedding and proteolytic activity.
In the second aim, wild type and transgenic mice with deletion of ADAM17 in myeloid-derived cells (LysM.Cre-
ADAM17fl/fl mice) will be used to determine the effect tissue-specific gene expression will have on the develop-
ment of PH in two models of disease (bleomycin-induced pulmonary fibrosis and chronic hypoxia). Upon com-
pletion, the contribution of this study will be significant because it represents a translatable strategy to improve
clinical outcomes through p...

## Key facts

- **NIH application ID:** 9886374
- **Project number:** 1R01HL142887-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Andrew Justin Bryant
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 1
- **Project period:** 2020-04-05 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886374

## Citation

> US National Institutes of Health, RePORTER application 9886374, Role of ADAM17 in MDSC-Mediated Development of Pulmonary Hypertension (1R01HL142887-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9886374. Licensed CC0.

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