Regulation of Platelet Glycoprotein (GP) Ib-IX Complex Function by Membrane Lipid

膜脂对血小板糖蛋白 (GP) Ib-IX 复合物功能的调节

基本信息

批准号：
8598506
负责人：
Yuandong Peng
金额：
$ 29.39万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-05 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8598506
关键词：
1-Phosphatidylinositol 3-Kinase Adhesions Bernard-Soulier Syndrome Binding Blood Platelets Cardiovascular Diseases Cell Communication Cell membrane Chinese Hamster Ovary Cell Cholesterol Complex Cytoplasmic Tail Data Disease Dissociation Disulfide Linkage Elements Event Excision Glycoprotein Ib Glycoproteins Glycosphingolipids Hemorrhage Hemostatic function In Vitro Individual Integrins Ligands Lipids Liquid substance Mediating Membrane Membrane Lipids Oxidation-Reduction Physiological Platelet Activation Platelet Glycoprotein GPIb-IX Complex Platelet Glycoproteins Play Process Protein Disulfide Isomerase Proteins Pseudo von Willebrand disease Regulation Reporting Role Signal Transduction Signaling Molecule Specific qualifier value Structure Surface Testing Thrombosis Thrombus Transgenic Mice Vision base combat in vivo injured insight novel novel therapeutics polypeptide public health relevance receptor research study shear stress src-Family Kinases von Willebrand Factor

项目摘要

DESCRIPTION (provided by applicant): The formation of platelet thrombi at shear stress is initiated by the binding of the platelet receptor, glycoprotein (GP) Ib-IX complex, to its ligand, von Willebrand factor (VWF). This receptor-ligand interaction is essential for tethering platelets to the injured vessel wall as a prerequisite for integrin-mediated firm arrest.Amalfunction in this interaction causes either Bernard-Soulier Syndrome (BSS) or platelet-type von Willebrand disease (VWD). It has long been thought that the GP Ib-IX complex/VWF interaction only provided the physical force to decelerate the flowing platelets. Recently, however, we have begun to realize that upon interacting with VWF, the GP Ib- IX complex can initiate transmembrane signaling events for integrin activation, leading to platelet firm adhesion and aggregation. Signaling molecules, such as Src family kinase, 14-3-3> and PI-3-Kinase, through association with the cytoplasmic domains of individual polypeptides, mediate these events. Lipid domains, also known as glycosphingolipid-enriched membranes (GEMs), can act as a platform for the assembly of downstream signaling molecules of the GP Ib-IX complex. Dissociation of the GP Ib-IX complex from the GEMs by membrane cholesterol depletion abolishes platelet activation and adhesion to VWF. Nevertheless, basic inquiries as to what the structural elements of the GP Ib-IX complex for GEMs association are, how such interaction is regulated, and what the physiological relevance of GEMs association in the GP Ib-IX function is, have never been answered. Our preliminary data demonstrate that GP Ib1 association with the GEMs domain is primarily mediated by GP Ib2/GP IX. Removal of disulfide linkage between GP Ib1 and GP Ib2/GP IX not only inhibits GP Ib1 association with GEMs domain, but also inhibits GP Ib-IX complex-expressing CHO (Chinese Hamster Ovary) cells interaction with VWF under high shear. In addition, we found that protein disulfide isomerase (PDI) associates with the GP Ib-IX complex in both platelets and the GP Ib-IX complex-expressing CHO cells, an interaction only being seen in GEMs domain. Furthermore, we demonstrated that alteration of platelet membrane lipid composition inhibits both GP Ib-IX complex association with GEMs domain and complex- mediated platelet interaction with VWF. Based on these results and previously reported evidence, we hypothesize that 1) GP Ib2/GP IX contains the structural determinants to mediate the GEMs interaction with the GP Ib-IX complex; 2) redox regulation by protein disulfide isomerase plays a role in the formation of disulfide linkage between GP Ib1 and GP Ib2/GP IX for GP Ib1 association with GEMs domain; 3) specific GEMs lipid composition is critical for complex association; and 4) specific disruption of GP Ib1 association with GEMs domain abolishes GP Ib-IX complex function. Overall, this proposed study will help to elucidate the structural basis for the proper localization of the GP Ib-IX complex on platelet surface, explore a novel mechanism for GP Ib-IX complex function regulation, and finally, to provide a mechanistic guide for developing novel therapeutic strategies to combat various complex related bleeding disorders and cardiovascular disease.

描述（由申请人提供）：剪切应力下的血小板血栓形成是由血小板受体糖蛋白（GP）IB-IX复合物与配体Von Willebrand因子（VWF）的结合引发的。这种受体配体相互作用对于将血小板绑定到受伤的血管壁是必不可少的，作为整联蛋白介导的公司逮捕的先决条件。在这种相互作用中，触及函数会导致伯纳德 - 苏利埃尔综合征（BSS）或血小板型型von von von von willbrand疾病（VWD）。长期以来，人们一直认为GP IB-IX复合物/VWF相互作用仅提供了减速流动血小板的物理力。但是，最近，我们开始意识到，与VWF相互作用后，GP IB-IX复合物可以启动整合素激活的跨膜信号事件，从而导致血小板企业的粘附和聚集。信号分子（例如SRC家族激酶，14-3-3>和PI-3-激酶）通过与单个多肽的细胞质结构域结合而介导这些事件，从而介导了这些事件。脂质结构域（也称为富含糖果脂酚）的膜（GEMS）可以充当GP IB-IX复合物的下游信号分子组装的平台。 GP IB-IX复合物与膜胆固醇消耗从宝石中解离，以消除了VWF的血小板激活和粘附。然而，关于GP IB-IX复合物的结构元素是什么，如何调节这种相互作用以及GP IB-IX功能中GEMS关联的生理相关性是什么，从未回答过什么，从未回答过GP IB-IX复合物的结构元素。我们的初步数据表明，GP IB1与GEMS域的关联主要由GP IB2/GP IX介导。去除GP IB1和GP IB2/GP IX之间的二硫键不仅抑制了GP IB1与GEMS结构域的关联，而且还抑制了GP IB-IX复合物表达CHO（中国仓鼠的Ovary）细胞在高剪切下与VWF的相互作用。此外，我们发现血小板和GP IB-IX复合物表达CHO细胞的蛋白二硫异构酶（PDI）与GP IB-IX复合物相关，仅在GEMS域中看到这种相互作用。此外，我们证明了血小板膜脂质组成的改变抑制了GP IB-IX复合物与GEMS结构域和与VWF的复杂介导的血小板相互作用。基于这些结果和先前报道的证据，我们假设1）GP IB2/GP IX包含结构决定因素，以介导与GP IB-IX复合物相互作用的GEMS相互作用； 2）蛋白质二硫异构酶调节氧化还原在GP IB1和GP IB2/GP IX之间的二硫键连接中起作用，用于GP IB1与GEMS域关联； 3）特定的宝石脂质成分对于复杂缔合至关重要； 4）GP IB1与GEMS域的特定破坏废除了GP IB-IX复杂函数。总体而言，这项拟议的研究将有助于阐明在血小板表面上适当定位GP IB-IX复合物的结构基础，探索用于GP IB-IX复合功能调节的新型机制，最后为开发新型的治疗策略提供机械指南，以打击各种相关的相关性出血性疾病和心血管疾病。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MicroRNAs 10a and 10b Regulate the Expression of Human Platelet Glycoprotein Ibα for Normal Megakaryopoiesis.

DOI：
10.3390/ijms17111873
发表时间：
2016-11-09
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Zhang Z;Ran Y;Shaw TS;Peng Y
通讯作者：
Peng Y

Defective Association of the Platelet Glycoprotein Ib-IX Complex with the Glycosphingolipid-Enriched Membrane Domain Inhibits Murine Thrombus and Atheroma Formation.

DOI：
10.4049/jimmunol.1501946
发表时间：
2016-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Zhou H;Ran Y;Da Q;Shaw TS;Shang D;Reddy AK;López JA;Ballantyne CM;Ware J;Wu H;Peng Y
通讯作者：
Peng Y

Inhibition of Hb Binding to GP1bα Abrogates Hb-Mediated Thrombus Formation on Immobilized VWF and Collagen under Physiological Shear Stress.

抑制 Hb 与 GP1bα 的结合可消除在生理剪切应力下固定 VWF 和胶原上 Hb 介导的血栓形成。