Subcellular mechanisms of platelet activation

血小板活化的亚细胞机制

基本信息

批准号：
8538671
负责人：
LAWRENCE F BRASS
金额：
$ 24.96万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2014-05-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8538671
关键词：
Accounting Affect Agonist Animal Model Anticoagulants Antiplatelet Drugs Behavior Biosensor Blood Circulation Blood Platelets Blood Vessels Blood flow Brain Collection Complex Data Defect Deposition Diamond Engineering Environment Ephrins Event Fibrin GTP-Binding Proteins Gap Junctions Goals Growth Health Heart Hemorrhage Hemostatic Agents Hemostatic function Home environment Human Image In Vitro Individual Injury Institution Investments Learning Life Maps Measures Methods Modeling Molecular Morphology Mus Myocardial Infarction National Center for Research Resources Pathway interactions Phosphotransferases Platelet Activation Play Porosity Principal Investigator Research Infrastructure Research Personnel Resolution Rest Schools Semaphorin-3 Shapes Signal Pathway Signal Transduction Site Stroke Structure Surface System Technology Testing Thrombin Thrombosis Thrombus Time Tissues Translating Work base brass density design flexibility gain of function mutation improved in vivo insight mouse model novel operation prevent receptor response sensor

项目摘要

DESCRIPTION (provided by applicant): Platelet accumulation is a hallmark of hemostasis and a contributor to heart attacks and strokes. In previous work, we and others have focused on identifying molecules that support platelet activation. Here we attempt a paradigm shift, approaching platelet activation as the product of a flexible signaling network rather than a collection of pathways, and joining testable ideas about the operation of that network to high resolution imaging of platelet activation in vivo. Our goal is to understand how the platelet signaling network shapes the hemostatic response and how the hemostatic response impacts the network. Our initial studies show that, rather than a homogeneous mass of platelets and fibrin, the response to penetrating injuries yields a hierarchical structure comprised of distinct regions that vary in the extent of platelet activation, packing density and porosity. A prominent feature is a core of fully-activated platelets overlaid with an unstable shell of less-activated platelets, but additional domains are present as well. Greater packing in the core allows adjacent platelets to interact, generating contact-dependent signals. Within the core is a region where thrombin activation and fibrin deposition occur. Our hypothesis is that all parts of this structure are subject to the platelet signaling network, with the core providing thrombus stabilit and gradients of soluble agonists determining the extent of thrombus growth and the size of the shell. Aim #1 will test and extend this model, applying additional activation markers, developing new methods for tracking individual platelets in vivo, and exploiting a newly- developed thrombin biosensor. Aim #2 will map relationships between the platelet signaling network and the structure of the hemostatic mass, and reassess the impact of anti-platelet agents in the context of a hierarchical model of hemostasis. Aim #3 will test the novel hypothesis that contact-dependent events are separated spatially and temporally into sets that either promote or restrain the thrombus core. Through these aims, we hope to determine why multiple agonists and signals are needed to shape an optimal platelet response, account for differences in the impact of antiplatelet agents, and show how pathological conditions can subvert normal responses by effects on the platelet signaling network.

描述（由申请人提供）：血小板积聚是止血的标志，也是导致心脏病和中风的一个因素。在之前的工作中，我们和其他人专注于识别支持血小板活化的分子。在这里，我们尝试进行范式转变，将血小板激活视为灵活信号网络的产物而不是途径的集合，并将有关该网络运行的可测试想法与体内血小板激活的高分辨率成像结合起来。我们的目标是了解血小板信号网络如何形成止血反应以及止血反应如何影响网络。我们的初步研究表明，对穿透性损伤的反应不是由血小板和纤维蛋白组成的均匀质量，而是产生由不同的层次结构组成的分层结构。血小板活化程度、堆积密度和孔隙率各不相同的区域。一个突出的特征是完全活化的血小板核心覆盖着活化程度较低的血小板的不稳定外壳，但也存在其他结构域。核心中更大的堆积允许相邻的血小板相互作用，产生接触依赖性信号。核心内是发生凝血酶激活和纤维蛋白沉积的区域。我们的假设是，该结构的所有部分都受到血小板信号网络的影响，核心提供血栓稳定性，可溶性激动剂的梯度决定血栓生长的程度和外壳的大小。目标#1将测试和扩展该模型，应用额外的激活标记，开发体内跟踪单个血小板的新方法，并利用新开发的凝血酶生物传感器。目标#2将绘制血小板信号网络与止血块结构之间的关系，并在止血分层模型的背景下重新评估抗血小板药物的影响。目标#3将测试新的假设，即接触依赖性事件在空间和时间上被分成促进或抑制血栓核心的集合。通过这些目标，我们希望确定为什么需要多种激动剂和信号来形成最佳血小板反应，解释抗血小板药物影响的差异，并展示病理条件如何通过影响血小板信号网络来破坏正常反应。