instrucUons): Platelets are important for hemostasis in response to vascular damage. Platelet deficiency or hypores?? ponsiveness results in excessive bleeding, whereas hyperactive platelets form pathological thrombi that can occlude blood vessels and cause myocardial infarction or stroke. It is therefore important to understand the mechanisms underlying platelet activation. Platelet activation at sites of vessel injury depends on cell surface adhesion and signaling receptors. Initial activation of platelets adhered to an injured blood vessel is mediated by the fliycofirotein Vl/Fc receptor x (GPVI/FcRy)-chain complex. Subsequent binding of plasma fibrinogen to the integrin allbpS on the activated platelet surface enables recruitment of additional platelets. Differences in the pathways through which GPVI/FcRy-chain and allbps activate platelets therefore offer opportunities for selective modulation of platelet accumulation at early vs. late stages of thrombus formation Activation of platelets via either GPVI or allbp3 requires participation by the cytosolic adaptor molecule, Src homology 2 (SH2) domain-containing jeukocyte grotein of 76 kDa (SLP-76), which coordinates assembly of a multi-molecular complex that activates a fihosphojipase C (PLC) y isoform. However, the domains of, and binding partners for, SLP-76 that support its recruitment to the membrane in GPVI-stimulated platelets are not utilized in allb/33-stimulated platelets.
Specific Aim 1 of this proposal seeks to determine whether the SH2 domain of SLP-76 and the non-T cell activation linker (NTAL) adaptor protein uniquely support flrllbyff3- mediated platelet activation. In addition, platelets express two isoforms of PLCy (yi and y2) and, whereas PLCy2 deficiency has been found to profoundly affect GPVI-mediated platelet activation, it has only mild effects on platelet activation by allbps.
SPECIFIC AIM 2 seeks to use newly-available conditionally PLCyl- deficient mice to determine whether PLC/I makes a more important contribution to allbyff3- than to GPVI- dependent responses. The proposed studies may therefore identify new signal transduction pathway components (NTAL or PLCyl), or new components of molecules that have long been known to participate in platelet signal transduction (SH2 domain of SLP-76), as novel targets for selective modulation of allbp3- dependent platelet accumulation in growing thrombi. The ultimate goal of clarifying unique components of the allbp3 signaling pathways is to enable fine-tuning of platelet adhesion and activation at sites of vascular injury so as to maximize control of bleeding and minimize thrombus growth.
Platelets circulate in the bloodstream and become activated when they encounter a damaged blood vessel. Activated platelets spread out and bind to one another so as to close up the damaged area and initiate wound healing. Our studies are designed to determine how platelet activation is controlled because excessive bleeding occurs when platelets are not active enough and heart attacks or strokes can occur when platelets are too active.
|Zeng, Hu; Yu, Mei; Tan, Haiyan et al. (2018) Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis. Sci Adv 4:eaar5701|
|Kanaji, Sachiko; Orje, Jennifer N; Kanaji, Taisuke et al. (2018) Humanized GPIb?-von Willebrand factor interaction in the mouse. Blood Adv 2:2522-2532|
|Baumgartner, C K; Mattson, J G; Weiler, H et al. (2017) Targeting factor VIII expression to platelets for hemophilia A gene therapy does not induce an apparent thrombotic risk in mice. J Thromb Haemost 15:98-109|
|Zhang, Nanyan; Zhi, Huiying; Curtis, Brian R et al. (2016) CRISPR/Cas9-mediated conversion of human platelet alloantigen allotypes. Blood 127:675-80|
|Chen, Yuhong; Zheng, Yongwei; You, Xiaona et al. (2016) Kras Is Critical for B Cell Lymphopoiesis. J Immunol 196:1678-85|
|Newman, Debra K; Fu, Guoping; Adams, Tamara et al. (2016) The adhesion molecule PECAM-1 enhances the TGF-?-mediated inhibition of T cell function. Sci Signal 9:ra27|
|Chen, Yingyu; Schroeder, Jocelyn A; Chen, Juan et al. (2016) The immunogenicity of platelet-derived FVIII in hemophilia A mice with or without preexisting anti-FVIII immunity. Blood 127:1346-54|
|Santoso, Sentot; Wihadmadyatami, Hevi; Bakchoul, Tamam et al. (2016) Antiendothelial ?v?3 Antibodies Are a Major Cause of Intracranial Bleeding in Fetal/Neonatal Alloimmune Thrombocytopenia. Arterioscler Thromb Vasc Biol 36:1517-24|
|Zhi, Huiying; Dai, Jing; Liu, Junling et al. (2015) Platelet Activation and Thrombus Formation over IgG Immune Complexes Requires Integrin ?IIb?3 and Lyn Kinase. PLoS One 10:e0135738|
|Liang, Hai Po H; Kerschen, Edward J; Basu, Sreemanti et al. (2015) Coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice. Blood 126:2415-23|
Showing the most recent 10 out of 229 publications