Injury to coronary, cerebral, and peripheral arteries evokes local platelet activation, recruitment, and thrombotic occlusion. Prevention and treatment of platelet-driven thrombus formation is a therapeutic challenge, with critical public health implications. In the presence of endothelial cells, platelets are unresponsive to agonists. This unrespon- siveness is due to endothelial NTPDasel/CD39/ecto-ADPase, which rapidly metabolizes ATP and ADP released from activated platelets. This abolishes aggregation and recruitment. Recombinant, soluble human CD39 (solCD39) blocks human platelet aggregation in v#ro, and inhibits porcine and routine platelet aggregation ex vivo. CD39 null mice exhibit a latent prothrombotic phenotype with increased susceptibility to stroke and cardiac and pulmonary thrombosis. This is alleviated in both wild-type and CD39 null mice by infusion of solCD39, demonstrating its critical role in thromboregulation. Broad, long-term objectives and specific aims include: I Molecular, biochemical and functional studies of human solCD39: Determination of the antithrombotic efficacy of selected mutants with increased ADP specificity/activity, and evaluation of the contribution of disulfide bridges to CD39 activity. 11Studies of the effects of NTPDases on cell-cell signaling during ischemia: Modulation of norepinephrine release by NTPDases from cardiac sympathetic nerve endings (cSNE) and isolated hearts from guinea pigs, wild type and CD39 null mice. Identification of the ecto-nucleotidase complement in cSNE from mouse and human heart, and assessment of pneumoprotection by endogenous and exogenous CD39 during second organ perfusion injury, inwild-type and CD39 null mice. I]1 Studies of NTPDase activities in lymphocytes from patients with angiographically documented coronary artery disease (CAD) to determine whether an altered, prothrombotic nucleotidase profile is expressed in comparison to that of lymphocytes from healthy donors. E Metabolism of adenosine derived from AMP as generated by CD39 from ATP and ADP: Can PRP metabolize AMP and generate inhibition of platelet reactivity by production of adenosine via 5'-nucleotidase? If true, is this dependent on specific platelet agonists, or on other blood or endothelial cells? Dioxin toxicity may involve increased catabolism of adenosine via upregulation of adenosine deaminase, thus reducing availability of adenosine, a potent platelet inhibitor. The research represents a multidisciplinary approach to understanding the critical role of CD39 as the prime regulator of platelet-mediated occlusive thrombosis. It is based on compelling feasibility data and historical collaborative success, and will advance the understanding of NTPDase biology and thromboregulation, culminating in a unique and novel therapeutic agent for thrombotic diatheses.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sarkar, Rita
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Aldi, Silvia; Marino, Alice; Tomita, Kengo et al. (2015) E-NTPDase1/CD39 modulates renin release from heart mast cells during ischemia/reperfusion: a novel cardioprotective role. FASEB J 29:61-9
Moeckel, Douglas; Jeong, Soon Soeg; Sun, Xiaofeng et al. (2014) Optimizing human apyrase to treat arterial thrombosis and limit reperfusion injury without increasing bleeding risk. Sci Transl Med 6:248ra105
Aldi, Silvia; Takano, Ken-ichi; Tomita, Kengo et al. (2014) Histamine H4-receptors inhibit mast cell renin release in ischemia/reperfusion via protein kinase C ?-dependent aldehyde dehydrogenase type-2 activation. J Pharmacol Exp Ther 349:508-17
Aldi, Silvia; Robador, Pablo A; Tomita, Kengo et al. (2014) IgE receptor-mediated mast-cell renin release. Am J Pathol 184:376-81
Chan, Noel Yan-Ki; Robador, Pablo A; Levi, Roberto (2012) Natriuretic peptide-induced catecholamine release from cardiac sympathetic neurons: inhibition by histamine H3 and H4 receptor activation. J Pharmacol Exp Ther 343:568-77
Robador, Pablo A; Seyedi, Nahid; Chan, Noel Yan-Ki et al. (2012) Aldehyde dehydrogenase type 2 activation by adenosine and histamine inhibits ischemic norepinephrine release in cardiac sympathetic neurons: mediation by protein kinase C?. J Pharmacol Exp Ther 343:97-105
Hashikawa-Hobara, Narumi; Chan, Noel Yan-Ki; Levi, Roberto (2012) Histamine 3 receptor activation reduces the expression of neuronal angiotensin II type 1 receptors in the heart. J Pharmacol Exp Ther 340:185-91
Marcus, Aaron J (2012) New approaches for measurement of platelet reactivity. Blood 119:3378-9
Chan, Noel Yan-Ki; Seyedi, Nahid; Takano, Kenichi et al. (2012) An unsuspected property of natriuretic peptides: promotion of calcium-dependent catecholamine release via protein kinase G-mediated phosphodiesterase type 3 inhibition. Circulation 125:298-307
Corti, Federico; Olson, Kim E; Marcus, Aaron J et al. (2011) The expression level of ecto-NTP diphosphohydrolase1/CD39 modulates exocytotic and ischemic release of neurotransmitters in a cellular model of sympathetic neurons. J Pharmacol Exp Ther 337:524-32

Showing the most recent 10 out of 56 publications