Genetic modulation of inflammation following myocardial infarction

PROJECT SUMMARY Following a myocardial infarction, an intense inflammatory response occurs whose duration and magnitude are modulated by CD4+CD25+Foxp3+ regulatory T cells (Tregs) that express CD39, an ectonucleotidase that degrades proinflammatory ATP and ADP. Immune responses are central to cardiac healing, and Tregs exert critical modulatory functions. Levels of immune-suppressive ectonucleotidase CD39 on Tregs are genetically controlled in humans by specific single nucleotide polymorphisms. However, no studies have examined whether differences in Treg CD39 activity impact cardiac inflammation resolution and healing following myocardial infarction in humans. In alignment with NOT-ES-20-018 “Notice of Special interest: Promoting Fundamental and Applied Research in Inflammation Resolution,” our overall experimental goal is to elucidate the impact of genetic regulation of Treg CD39 expression on the resolution of cardiac inflammation following myocardial infarction. Our recent publication demonstrates that post-myocardial infarction healing in mice devoid of CD39 expression is dysfunctional, with increased fibrosis and worsening diastolic function. However, CD39 is expressed in several immune cells and endothelial cells; therefore, in this model, no conclusions can be drawn regarding which CD39- expressing cell subset is instrumental in regulating cardiac healing. Our critical data demonstrate that in humans, the genotype at the ENTPD1 promoter SNP rs3814159 associates with the level of expression of CD39 on Tregs. Given the evolving role of Tregs in modulating post-MI inflammation and healing, our central hypothesis is that genetic polymorphisms resulting in decreased Treg CD39 activity convey a pro-inflammatory phenotype that fails to resolve chronic inflammatory conditions. We will test this hypothesis by conducting functional genomic experiments using novel murine experimental model systems and clinical studies, examining isolated cells and patient biospecimens. The proposal consists of two Aims. In SA1, our investigative team will determine how CD39 activity on T regulatory cells impacts cardiac inflammation resolution and myocardial healing following myocardial infarction. This will be done using murine models of reduced and ablated expression of CD39 on Tregs. In SA2, we will determine the impact of differences in CD39 expression on the inflammatory response and resolution following myocardial infarction in humans. We have assembled a collaborative team with clinical and experimental cardiovascular disease, genetics, and biostatistics expertise. Completing the proposed aims will provide an understanding of the role of the genetically predetermined expression of CD39 on Tregs in cardiac inflammation and inflammatory resolution. Translation to clinical practice will be facilitated by identifying important biomarkers and novel targets, including CD39 and related pathways, for therapeutic intervention in myocardial infarction.