Cardiovascular disease (CVD) is the leading cause of death in the US annually, accounting for nearly 1 in 3 deaths and over $500 billion in annual health care cost in the US. Platelet-mediated thrombosis is the primary underlying mechanism leading to cardiovascular life-threatening clinical events, such as stroke or myocardial infarction One form of platelet-mediated thrombosis is through the immune-complex activation of Fc?RIIa (a transmembrane receptor containing ITAM in the cytoplasmic tail). The activation of Fc?RIIa is responsible for immune-mediated thrombocytopenia and thrombosis, which can often lead to life-threatening cardiovascular related complications in patients who receive heparin or experience sepsis. Platelet 12-lipoxygenase (12-LOX) has been demonstrated to be an essential modulator of Fc?RIIa-mediated platelet activation; however, the underlying signaling mechanism by which 12-LOX regulates the Fc?RIIa signaling is still unclear. Understanding the signaling mechanisms by which 12-LOX regulates this pathway is a critical step in validating its role as a potential and effective anti-platelet target for the prevention of immune-mediated thrombotic events. For this proposal, I will aim to 1) elucidate the underlying mechanisms by which 12-LOX regulates the Fc?RIIa-mediated activation in platelets. The role of 12-hydroxyeicosatetraenoic acid (12-HETE), the predominant 12-LOX oxidized lipid, and potential protein binding partners of 12-LOX will be investigated and identified in the Fc?RIIa signaling pathway. These studies will provide valuable and deeper insights in the biochemical roles of 12-LOX in the Fc?RIIa-mediated platelet activation pathway.
Aim will 2) Characterize the role of 12-LOX in vivo by utilizing transgenic mice expressing humanized Fc?RIIa and deficient in 12-LOX (hFcR/ALOX12-/-) compared to the normal 12-LOX model (hFcR/ALOX12+/+). The in vivo approaches will aid in determining whether 12-LOX proves to be an efficient target in treating and limiting immune-mediated thrombocytopenia and as well preventing thrombosis. Elucidating the underlying mechanisms by which 12- LOX and its oxylipin regulate Fc?RIIa-mediated platelet function is crucial in order to accelerate the rational design of novel therapeutics for immune-mediated disorders involving incidence of thrombotic occlusion.

Public Health Relevance

12?Lipoxygenase potentiates platelet reactivity, leading to unwanted thrombosis and blood clot formation. Additionally, 12?lipoxpoygenase has been proposed to be a viable target in regulating Fc?RIIa-mediated platelet activation and thrombosis. In order to validate 12?LOX As a therapeutic target, the signaling mechanisms by which 12-LOX impinge on the Fc?RIIa signaling pathway must be elucidated.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Chang, Henry
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University of Michigan Ann Arbor
Ann Arbor
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Tourdot, Benjamin E; Stoveken, Hannah; Trumbo, Derek et al. (2018) Genetic Variant in Human PAR (Protease-Activated Receptor) 4 Enhances Thrombus Formation Resulting in Resistance to Antiplatelet Therapeutics. Arterioscler Thromb Vasc Biol 38:1632-1643
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Adili, Reheman; Tourdot, Benjamin E; Mast, Katherine et al. (2017) First Selective 12-LOX Inhibitor, ML355, Impairs Thrombus Formation and Vessel Occlusion In Vivo With Minimal Effects on Hemostasis. Arterioscler Thromb Vasc Biol 37:1828-1839
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Yeung, Jennifer; Tourdot, Benjamin E; Adili, Reheman et al. (2016) 12(S)-HETrE, a 12-Lipoxygenase Oxylipin of Dihomo-?-Linolenic Acid, Inhibits Thrombosis via G?s Signaling in Platelets. Arterioscler Thromb Vasc Biol 36:2068-77