The platelet membrane glycoprotein Ib-IX complex (GPIb-IX) plays an important role in platelet adhesion, particularly in arteries and capillaries. At sites of vascular injury, GPIb-IX interacts with the subendothelium-bound von Willebrand factor (VWF). This interaction not only mediates the physical adherence of platelets to the site of vascular injury, but also initiates signaling. GPIb-IX-mediated signaling leads to the cytoskeleton reorganization and activation of the ligand binding function of the platelet integrin aIIbB3 that mediates stable platelet adhesion, spreading and aggregation. This process is critical in both hemostasis and thrombosis. VWF binding to GPIb-IX also induces release of platelet microparticles that facilitates coagulation. Under certain pathological conditions such as thrombotic thrombocytopenic purpura (TTP), binding of GPIb-IX to circulating ultra-large VWF multimers induces microthrombosis and development of microthrombopathy. The overall goals of this project are to understand the signaling mechanism of GPIb-IX in thrombosis, platelet activation and cytoskeleton organization, and to explore the possibility of developing GPIb-IX-based therapeutic approaches. In the last 3 years'since the previous renewal, we have made significant progresses in understanding the regulatory role of 14-3-3 in GPIb function, developed an in vivo inhibitor delivery method allowing testing the in vivo effects of 14-3-3 inhibitor on GPIb function and thrombus formation, and delineated a novel Lyn-PI3K- Akt1/Akt2-NO-cGMP signaling pathway as an early signaling mechanism leading to integrin activation and stable platelet adhesion under shear stress. Furthermore, we have obtained substantial amount of preliminary data that forms the basis of new hypotheses for the specific aims of this competitive renewal. We propose following specific aims:
Aim 1, to determine the role of GPIb-IX and 14-3-3 in thrombosis and microvascular thrombosis in sepsis and TTP and to explore the therapeutic effect of an inhibitor of GPIb-IX-14-3-3 interaction;
Aim 2, to investigate the role of LIMK1 in GPIb-IX-mediated platelet activation and cytoskeleton reorganization;
and Aim 3, to determine the role of Rac1 in GPIb-IX-mediated signaling leading to platelet activation and microparticle release.
A receptor molecule on the surface of blood platelets, named glycoprotein Ib-IX, mediates adhesion of blood platelets to blood vessel wall, and is important in preventing excessive bleeding when blood vessels are injured. This molecule is also important in thrombosis, that is """"""""clotting"""""""" in blood vessels causing heart attack and stroke. This research project is to study how glycoprotein Ib-IX initiates platelet adhesion and """"""""clotting"""""""". We will also investigate whether this molecule participates in the formation of small clots in patients suffering from severe sepsis, and develop a new drug that may potentially be useful in treating clotting in patients suffering from heart attack, stroke and sepsis.
|Estevez, Brian; Du, Xiaoping (2017) New Concepts and Mechanisms of Platelet Activation Signaling. Physiology (Bethesda) 32:162-177|
|Delaney, M Keegan; Kim, Kyungho; Estevez, Brian et al. (2016) Differential Roles of the NADPH-Oxidase 1 and 2 in Platelet Activation and Thrombosis. Arterioscler Thromb Vasc Biol 36:846-54|
|Estevez, Brian; Kim, Kyungho; Delaney, M Keegan et al. (2016) Signaling-mediated cooperativity between glycoprotein Ib-IX and protease-activated receptors in thrombin-induced platelet activation. Blood 127:626-36|
|Ju, Lining; Chen, Yunfeng; Xue, Lingzhou et al. (2016) Cooperative unfolding of distinctive mechanoreceptor domains transduces force into signals. Elife 5:|
|Estevez, Brian; Shen, Bo; Du, Xiaoping (2015) Targeting integrin and integrin signaling in treating thrombosis. Arterioscler Thromb Vasc Biol 35:24-9|
|Shen, Bo; Estevez, Brian; Xu, Zheng et al. (2015) The interaction of G?13 with integrin ?1 mediates cell migration by dynamic regulation of RhoA. Mol Biol Cell 26:3658-70|
|Delaney, Michael Keegan; Liu, Junling; Kim, Kyungho et al. (2014) Agonist-induced platelet procoagulant activity requires shear and a Rac1-dependent signaling mechanism. Blood 124:1957-67|
|Rusu, Luiza; Andreeva, Alexandra; Visintine, David J et al. (2014) G protein-dependent basal and evoked endothelial cell vWF secretion. Blood 123:442-50|
|Li, Jing; Kim, Kyungho; Hahm, Eunsil et al. (2014) Neutrophil AKT2 regulates heterotypic cell-cell interactions during vascular inflammation. J Clin Invest 124:1483-96|
|Estevez, Brian; Stojanovic-Terpo, Aleksandra; Delaney, M Keegan et al. (2013) LIM kinase-1 selectively promotes glycoprotein Ib-IX-mediated TXA2 synthesis, platelet activation, and thrombosis. Blood 121:4586-94|
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