Clinically significant thrombotic events are common complications of many systemic diseases associated with chronic inflammation, including atherosclerosis and diabetes. Many of these life- threatening thrombi occur in the arterial circulation and relate to inappropriate platelet activation. This proposal will test the novel hypothesis that the type B scavenger receptor CD36 functionally links metabolic and oxidant stress to platelet "hyper-reactivity" and thus to the increased risk of thrombosis. Published and preliminary studies using mouse thrombosis models and primary human and mouse cells identified CD36 as a platelet signaling receptor that recognizes and responds to endogenous "danger signals" generated during inflammation, including oxidized LDL, advanced glycated proteins, and cell-derived microparticles. A specific CD36-triggered signaling pathway in platelets involving recruitment/assembly of an activated signaling complex made up of Src kinases, MAP kinases, and Vav family guanine nucleotide exchange factors was identified and shown to be unique from other platelet pathways. This proposal will test the hypothesis that signaling cascades triggered by CD36 engagement with "danger signal" ligands promote a unique "hypersensitive" platelet phenotype that contributes to a pro-thrombotic state in vivo. The mechanisms by which CD36 activates specific platelet signaling pathways to regulate cytoskeletal functions and oxidative stress will be defined. Sophisticated imaging systems using a microfluidic in vitro model of platelet function under shear and novel in vivo thrombosis models will be exploited to connect CD36-specific signaling pathways to the mechanisms of the related pro-thrombotic effect. Reciprocal influences of other platelet pro- and anti-activation pathways on the CD36 pathway will be defined to reveal novel synergies and interactions. In vivo models will be used to test the hypothesis that CD36-specific endogenous danger signal ligands promote thrombosis via functional interactions with toll like receptors and the cell-specific role f CD36 in promoting thrombosis in vivo in the setting of metabolic and oxidant stress will be determined using targeted genetic deletion and bone marrow transplantation strategies with in vivo models of inflammation and thrombosis.
Thrombosis (blood clots) is the leading cause of morbidity and mortality in the United States. Inappropriate activation of blood platelets, the main cellular initiator of thrombosis, is a major cause of thrombosis. This Project seeks to identify and characterize the mechanisms by which blood abnormalities generated during chronic inflammatory conditions, such as diabetes and atherosclerosis, alter platelet function through interacting with a specific protein, CD36, on the surface of platelets. Identification of new ways platelets respond to inflammatory mediators offers new sites of therapeutic interventions.
|Ramakrishnan, Devi Prasadh; Hajj-Ali, Rula A; Chen, Yiliang et al. (2016) Extracellular Vesicles Activate a CD36-Dependent Signaling Pathway to Inhibit Microvascular Endothelial Cell Migration and Tube Formation. Arterioscler Thromb Vasc Biol 36:534-44|
|Zhu, Weifei; Gregory, Jill C; Org, Elin et al. (2016) Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 165:111-24|
|Hajj-Ali, Rula A; Major, Jennifer; Langford, Carol et al. (2015) The interface of inflammation and subclinical atherosclerosis in granulomatosis with polyangiitis (Wegener's): a preliminary study. Transl Res 166:366-74|
|Chen, Yiliang; Kennedy, David J; Ramakrishnan, Devi Prasadh et al. (2015) Oxidized LDL-bound CD36 recruits an Naâº/Kâº-ATPase-Lyn complex in macrophages that promotes atherosclerosis. Sci Signal 8:ra91|
|Silverstein, Roy L (2015) Disabling the platelet's brakes to promote thrombosis. Blood 125:2591-3|
|Chadwick, Alexandra C; Holme, Rebecca L; Chen, Yiliang et al. (2015) Acrolein impairs the cholesterol transport functions of high density lipoproteins. PLoS One 10:e0123138|
|Simon, Daniel I; Silverstein, Roy L (2015) Atherothrombosis: Seeing Red? Circulation 132:1860-2|
|Li, Wei; Gigante, Alba; Perez-Perez, Maria-Jesus et al. (2014) Thymidine phosphorylase participates in platelet signaling and promotes thrombosis. Circ Res 115:997-1006|
|Silverstein, Roy L (2014) Platelet CD36 links not only Î±-granule-derived proteins to thrombus stability but also metabolic and oxidant stress to a prothrombotic phenotype. Arterioscler Thromb Vasc Biol 34:1120-1|
|Wang, Yunmei; Fang, Chao; Gao, Huiyun et al. (2014) Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis. J Clin Invest 124:2160-71|
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