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:8038383
- 负责人:
- 金额:$ 30.3万
- 依托单位:
- 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 2014-12-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAdhesionsBernard-Soulier SyndromeBindingBlood PlateletsCardiovascular DiseasesCell CommunicationCell membraneChinese Hamster Ovary CellCholesterolComplexCytoplasmic TailDataDiseaseDissociationDisulfide LinkageElementsEventExcisionGlycoprotein IbGlycoproteinsGlycosphingolipidsHemorrhageHemostatic functionIn VitroIndividualIntegrinsLigandsLipidsLiquid substanceMediatingMembraneMembrane LipidsOxidation-ReductionPhysiologicalPlatelet ActivationPlatelet Glycoprotein GPIb-IX ComplexPlatelet GlycoproteinsPlayProcessProtein Disulfide IsomeraseProteinsPseudo von Willebrand diseaseRegulationReportingRoleSignal TransductionSignaling MoleculeSpecific qualifier valueStructureSurfaceTestingThrombosisThrombusTransgenic MiceVisionbasecombatin vivoinjuredinsightnovelnovel therapeuticspolypeptidepublic health relevancereceptorresearch studyshear stresssrc-Family Kinasesvon 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.
PUBLIC HEALTH RELEVANCE: Platelet membrane lipid domain is important for platelet function in thrombosis and haemostasis. The platelet glycoprotein GP Ib-IX complex is one of the proteins regulated by membrane lipid domain. In this project, we sight to investigate this regulatory mechanism.
描述(由申请方提供):血小板受体(糖蛋白(GP)Ib-IX复合物)与其配体(血管性血友病因子(VWF))结合,在剪切应力下引发血小板血栓形成。这种受体-配体相互作用是将血小板束缚在受损血管壁上的必要条件,是整合素介导的牢固停滞的先决条件,这种相互作用的功能障碍可引起Bernard-Soulier综合征(BSS)或血小板型血管性血友病(VWD)。长期以来,人们一直认为GP Ib-IX复合物/VWF相互作用仅提供使流动的血小板减速的物理力。然而,最近我们开始认识到,在与VWF相互作用时,GP Ib- IX复合物可以启动跨膜信号传导事件,从而激活整联蛋白,导致血小板牢固粘附和聚集.信号分子,如Src家族激酶、14-3-3>和PI-3-激酶,通过与单个多肽的胞质结构域结合,介导这些事件。脂质结构域,也称为鞘糖脂富集膜(GEM),可以作为GP Ib-IX复合物下游信号分子组装的平台。GP Ib-IX复合物通过膜胆固醇耗竭从GEM解离,消除了血小板活化和与VWF的粘附。然而,基本的查询,什么样的结构元素的GP Ib-IX复杂的GEM协会,这种相互作用是如何调节,以及什么样的生理相关性的GEM协会在GP Ib-IX功能,从来没有得到回答。我们的初步数据表明,GP Ib 1与GEM结构域的关联主要是由GP Ib 2/GP IX介导的。去除GP Ib 1和GP Ib 2/GP IX之间的二硫键不仅抑制了GP Ib 1与GEM结构域的结合,而且抑制了表达GP Ib-IX复合物的CHO细胞在高剪切下与VWF的相互作用。此外,我们发现蛋白质二硫键异构酶(PDI)与GP Ib-IX复合物在血小板和表达GP Ib-IX复合物的CHO细胞中结合,仅在GEM结构域中观察到相互作用。此外,我们证明了血小板膜脂质组成的改变抑制GP Ib-IX复合物与GEM结构域的结合以及复合物介导的血小板与VWF的相互作用。基于这些结果和已有的证据,我们推测:1)GP Ib 2/GP IX含有介导GEM与GP Ib-IX复合物相互作用的结构决定簇:2)二硫键异构酶的氧化还原调节在GP Ib 1与GP Ib 2/GP IX之间形成二硫键以使GP Ib 1与GEM结合; 3)特异性GEM脂质组成对于复合物缔合是关键的;和4)GP Ib 1与GEM结构域缔合的特异性破坏消除了GP Ib-IX复合物功能。总之,这项研究将有助于阐明GP Ib-IX复合物在血小板表面正确定位的结构基础,探索GP Ib-IX复合物功能调节的新机制,并最终为开发新的治疗策略提供机制指导,以对抗各种复杂的出血性疾病和心血管疾病。
公共卫生相关性:血小板膜脂质结构域对血栓形成和止血中的血小板功能很重要。血小板糖蛋白GP Ib-IX复合物是受膜脂结构域调控的蛋白质之一。在本项目中,我们着眼于研究这种调节机制。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Yuandong Peng其他文献
Yuandong Peng的其他文献
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{{ truncateString('Yuandong Peng', 18)}}的其他基金
ROLES FOR CASEIN KINASE 2 IN KINETOCHORE REGULATION
酪蛋白激酶 2 在动粒调节中的作用
- 批准号:
8171239 - 财政年份:2010
- 资助金额:
$ 30.3万 - 项目类别:
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
- 批准号:
7783032 - 财政年份:2010
- 资助金额:
$ 30.3万 - 项目类别:
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
- 批准号:
8210830 - 财政年份:2010
- 资助金额:
$ 30.3万 - 项目类别:
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
- 批准号:
8403649 - 财政年份:2010
- 资助金额:
$ 30.3万 - 项目类别:
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
- 批准号:
8598506 - 财政年份:2010
- 资助金额:
$ 30.3万 - 项目类别:
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