Project Details
Description
PROJECT SUMMARY
Atherosclerotic cardiovascular disease (ASCVD) is an inflammatory disease of unclear pathogenesis that
remains the leading cause of morbidity and mortality throughout the world. Immune responses play a central role
in the evolution of this chronic disease, and CD4+CD25+Foxp3+ regulatory T cells (Tregs) exhibit critical functions
to regulate inflammation. We have shown the level of expression of CD39, an immunosuppressive
ectonucleotidase, on Tregs to be genetically associated in humans with specific single nucleotide polymorphisms
(SNPs). Although select SNPs for CD39 have been linked to Crohn disease, no studies have examined whether
alterations in Treg CD39 catalytic activity, and changes in extracellular ATP scavenging with adenosine
generation, impact manifestations of ASCVD. Similarly, a naturally occurring antisense ENTPD1-AS1 has been
shown to decrease CD39 expression in Crohn’s patient Tregs. Inhibition of ENTPD1-AS1 with a specific self-
delivering FANA CD39 antisense (FANA-CD39-AS) oligonucleotide were shown to increase CD39 expression,
providing a therapeutic option to modulate Treg phenotype. Our overall experimental goal is to elucidate the
impact of genetic regulation of Treg CD39 expression in ASCVD. The central hypothesis is that genetic mutations
resulting in decreased Treg CD39 activity and altered purinergic responses drive ASCVD due to the inability to
adequately resolve inflammation. We will test this hypothesis by conducting functional genomic experiments, in
addition to using novel murine experimental model systems, and develop clinical studies, examining isolated
cells and patient biospecimens. The proposal consists of two Aims. In SA1, our investigative team will determine
how Treg expression of CD39 activity impacts atherosclerosis in a validated experimental system. This will be
done using CD39 Treg-specific conditional knock-down and knockout murine models with multiple readouts of
T cell and myeloid activation responses, and adoptive transfer studies, In SA2, we will examine the regulation of
CD39 expression on human Tregs and examine the impact of CD39 modulation on immune function and
inflammation in clinical studies of ASCVD. We have assembled a collaborative team with clinical and
experimental expertise in ASCVD, immunology, vascular biology, genetics, and biostatistics. Completion of the
proposed aims will develop understanding of the role of Tregs, and specifically expression of CD39 and altered
purinergic responses, in ASCVD, this most important and significant disease. Translation to clinical practice will
be facilitated by identification of important biomarkers and novel targets, inclusive of CD39 and related pathways
of adenosinergic signaling, for therapeutic intervention in ASCVD.
Status | Active |
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Effective start/end date | 06/1/23 → 05/31/24 |
Funding
- National Heart, Lung, and Blood Institute: $741,684.00
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