# Purinergic regulation of Innate Immunity to promote Venous Homeostasis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $447,978

## Abstract

ABSTRACT
Deep venous thrombosis (DVT) and secondary pulmonary embolism (together, VTE) affect 900,000
Americans, and result in >60,000 deaths each year. A growing body of evidence supports the concept of
crosstalk between inflammation and coagulation which amplifies the thrombo-inflammatory response in VTE.
Activated, injured, and dying cells release nucleotides that form purinergic halo of “danger” signals that disrupt
vascular homeostasis. Located on the surface of leukocytes and the endothelium, the vascular
ectonucleotidase, CD39 rapidly phosphohydrolyzes ATP, and ADP to extinguish these “danger” signals and
promote homeostasis. We have found that CD39 is a potent suppressor of the thrombo-inflammatory response
in DVT. Our new preliminary data show that CD39 inhibits circulating leukocyte-platelet interactions, and
restricts activation of programmed innate immune responses, including inflammasome assembly and
neutrophil extracellular trap (NET) formation, key drivers of the growing thrombus. The hypothesis driving this
work is that CD39 provides a critical vascular checkpoint at the intersection of innate immunity and thrombosis
to arrest the relentless venous thrombo-inflammatory cycle. Using unique cell lineage (myeloid, neutrophil,
endothelial)-specific CD39 gene-deleted mice we have generated, and complementary models of DVT, we will:
1) Elucidate the role for CD39 on cellular recruitment during venous thrombogenesis and maturation. These
experiments will define the effect of lineage-specific CD39 on blood cell recruitment, and the spatial dynamics
of their interactions during venous thrombogenesis; 2) Determine the mechanism(s) by which myeloid CD39
protects against venous thrombo-inflammation. These experiments will determine the contributions of
macrophage and neutrophil CD39 to venous thrombosis. Complementary in vitro and in vivo studies with
genetically-modified mice will elucidate the molecular signaling processes by which CD39 inhibits
inflammasome activation during thrombogenesis; 3) Determine the effect of CD39-deficiency on microvesicle
phenotype, function, and kinetics, during venous thrombosis. These studies will reveal the functional
consequences of altering global- and lineage-specific CD39 on microvesicle-mediated thrombo-inflammatory
signaling. These studies should yield new insights into how an ectonucleotidase that functions as a checkpoint
at the intersection of thrombosis and inflammation may be exploited to improve treatments in venous
thrombosis.

## Key facts

- **NIH application ID:** 10120726
- **Project number:** 5R01HL150392-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** David J. Pinsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $447,978
- **Award type:** 5
- **Project period:** 2020-03-05 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120726

## Citation

> US National Institutes of Health, RePORTER application 10120726, Purinergic regulation of Innate Immunity to promote Venous Homeostasis (5R01HL150392-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10120726. Licensed CC0.

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