The number of known novel platelet receptors/ligands that regulate the platelet activation cascade is growing. Recent studies demonstrated that scavengejr receptor class B, type I (SR-BI) is expressed on human and murine platelets. Importantly, reduced levels of platelet SR-BI expression are associated with increased platelet aggregation in patients. Total SR-Bl deficiency in mice on an apoE null background results in spontaneous myocardial infarction and premature death. Our preliminary studies showed that deficiency of SR-BI in murine platelets is also associated with remarkably increased platelet activation and aggregation in response to selected physiological agonists. In addition, we recently identified specific ligands for SR-BI that are potent inhibitors of integriri allbps activation andplatelet aggregation in vitro. Mechanisms linking SR-BI and allbB33 activation areniknown. Control of platelet reactivity is regarded as critical for prevention of acute cardiovascular events, thus the elucidation of mechanisms by which SR-BI may regulate integrin activation and whether it contributes to thrombotic events in vivo is important. It has been established that SR-BI may participate in signa ing events in several cell types. Moreover, CD36, a close relative of SR-BI, is associated in platelets wit i several protein-tyrosine kinases of theSrc family, Thus, we hypothesized that SR-BI-mediated signaling in platelets controls platelet integrin allbpS activation and, therefore, platelet aggregation and thrombosis. T ie long-term goal of this proposal is to determine the role platelet SR-BI is playing in thrombosis and to eluc date the exact molecular and cellular mechanisms of its contribution.
The specific Aims are:
Aim 1. To characterize the role cif SR-BI in integrin allb(33 activation andplatelet function in vitro.
Aim II. Toidentify the molecular signaling mechanisms linking SR-BI and activation of integrin allbft3 in platelets.
Aim III. Wewillseek to obtain evidence that platelet SR-BIplays a significant role in the regulation of platelet activation and thrombosis in vivo.
|Zimman, Alejandro; Titz, Bjoern; Komisopoulou, Evangelia et al. (2014) Phosphoproteomic analysis of platelets activated by pro-thrombotic oxidized phospholipids and thrombin. PLoS One 9:e84488|
|Plow, Edward F; Das, Mitali (2014) Rising like the phoenix? Arterioscler Thromb Vasc Biol 34:2182-3|
|Sossey-Alaoui, Khalid; Pluskota, Elzbieta; Davuluri, Gangarao et al. (2014) Kindlin-3 enhances breast cancer progression and metastasis by activating Twist-mediated angiogenesis. FASEB J 28:2260-71|
|Soloviev, Dmitry A; Hazen, Stanley L; Szpak, Dorota et al. (2014) Dual role of the leukocyte integrin ?M?2 in angiogenesis. J Immunol 193:4712-21|
|Das, Mitali; Subbayya Ithychanda, Sujay; Qin, Jun et al. (2014) Mechanisms of talin-dependent integrin signaling and crosstalk. Biochim Biophys Acta 1838:579-88|
|Davuluri, Gangarao; Augoff, Katarzyna; Schiemann, William P et al. (2014) WAVE3-NF?B interplay is essential for the survival and invasion of cancer cells. PLoS One 9:e110627|
|Plow, Edward F; Meller, Julia; Byzova, Tatiana V (2014) Integrin function in vascular biology: a view from 2013. Curr Opin Hematol 21:241-7|
|Gao, Detao; Willard, Belinda; Podrez, Eugene A (2014) Analysis of covalent modifications of proteins by oxidized phospholipids using a novel method of peptide enrichment. Anal Chem 86:1254-62|
|Yang, Jun; Zhu, Liang; Zhang, Hao et al. (2014) Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion. Nat Commun 5:5880|
|Kerr, B A; McCabe, N P; Feng, W et al. (2013) Platelets govern pre-metastatic tumor communication to bone. Oncogene 32:4319-24|
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