PROJECT SUMMARY/ABSTRACT The mammalian heart possesses a poor ability to regenerate after myocardial infarction and heals via a fibrotic repair response. Scar tissue increases the hemodynamic burden on the remaining cardiac muscle and over time, the ventricle fails leading to the development of heart failure. Myocardial infarction contributes to almost 40-70% of all cases of heart failure and 700,000 patients are annually diagnosed with heart failure in the United States alone. The main thrust of cardiovascular pharmacology for the treatment /prevention of heart failure after heart attacks has centered on chronic antagonism of the sympatho-adrenal-angiotensin- aldosterone axis (Beta blockers, ACE inhibitors, Angiotensin receptor blockers and aldosterone antagonists) but despite available pharmacological therapies, the 5 year survival rate of heart failure is less than 50%. There thus exists an immense unmet need to identify novel pharmacological strategies for the treatment and prevention of heart failure. We have recently demonstrated the role of a specific ectonucleotidase, ENPP1 (ectonucleotide pyrophosphatase/ phosphodiesterase 1) in cardiac repair following myocardial infarction. ENPP1 is induced by orders of magnitude after myocardial infarction and show that hydrolytic products generated by ectonucleotidase activity contribute to inflammation and impair the cardiac injury response. Using genetic loss of function approaches, we showed that inhibition of ENPP1 in the infarcted heart leads to decreased non- myocyte cell death, decreased inflammation and significantly superior post infarct cardiac function. Considering these observations, in collaboration with an antibody engineering biotech company, we in this proposal have engineered a humanized monoclonal antibody targeting ENPP1 as a therapeutic biologic to treat post infarct decline in cardiac function. We provide proof of concept efficacy studies demonstrating the ability of the administered clinical candidate to modulate inflammation in the infarcted heart and lead to significantly better preservation of post infarct function and decreased post infarct ventricular remodeling. Further development of the monoclonal antibody combined with definitive preclinical studies in humanized mice models as well as large animal infarct models forms the substance of the proposal. Using a variety of “omics” approaches and genetically engineered mice, we will also interrogate in depth the downstream pathways that are affected by the ENPP1mAb to exert salutary effects on cardiac repair and post infarct heart function. If our studies are successful, the proposal will directly lead to the identification of a clinical monoclonal antibody candidate to attenuate post infarct cardiac remodeling and dysfunction.