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Notice: Historical Content
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Grant Abstract: Purinergic modulation of the autoimmune vascular phenotype

Grant Number: 5R01HL134846-03
PI Name: Knight
Project Title: Purinergic modulation of the autoimmune vascular phenotype

Abstract: Dead and dying cells release purine nucleotides, which then engage nucleotide receptors on the surfaces of leukocytes and endothelial cells to trigger inflammation, coagulation, and vasoconstriction. To counter these chemical mediators of vascular disequilibrium, leukocytes and endothelial cells express surface ectonucleotidases (CD39 and CD73) that catalyze the step-wise phosphohydrolysis of ATP into adenosine—thereby creating an anti-inflammatory and antithrombotic halo of adenosine around the cell. In patients with systemic lupus erythematosus (commonly referred to as lupus), stroke and venous thrombosis are relentlessly driven by oxidative stress and prothrombotic autoantibodies. Furthermore, our laboratory recently discovered that neutrophil extracellular traps (NETs, tangles of chromatin expelled from activated neutrophils via a program coined NETosis) trigger endothelial damage and in situ thrombosis in lupus. The NHLBI-supported parent project has been in pursuit of the hypothesis that CD73 and its downstream pathways serve as endogenous (and potentially amplifiable) counterpoints to hyperactive lupus neutrophils. Indeed, work to date on the parent project has revealed that CD73 deficiency accelerates NETosis, dysfunction of the arterial endothelium, and venous thrombosis in mouse models of lupus. Mechanistic studies have determined that agonism of the adenosine A2A receptor is particularly important to the anti-inflammatory effects of the CD73 pathway. Specifically, A2A agonists turn on adenylate cyclase, which increases intracellular levels of cyclic AMP (cAMP) and thereby suppresses neutrophil activation including NETosis. Preliminary data supported by University of Michigan resources have now revealed that the natural dietary supplement 6-gingerol is a highly effective inducer of cAMP in lupus neutrophils. Mechanistically, 6-gingerol appears to block intracellular phosphodiesterase activity. This raises the possibility that 6-gingerol will function as a natural counterpoint to the CD73-deficient state—a state that, as above, exacerbates lupus. In summary, while preserving the parent grant’s focus on CD73 and lupus, this supplementary research will differ from the parent grant—extending its impact and scope—by investigating the effectiveness of 6-gingerol in the prevention of NETosis and vascular events in models of CD73 deficiency and lupus. Our group is ideally positioned to reveal the cellular and molecular mechanisms by which 6-gingerol acts on neutrophils, with an eye toward future studies that might administer ginger supplements to humans known to be at high risk for autoimmune conditions and/or cardiovascular disease (for example, individuals with autoantibodies who have yet to have clinical events, or patients with cardiovascular risk factors such as hypertension and diabetes).

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