BLOOD COAGULATION FACTORS

凝血因子

• 批准号: 8361087
• 负责人: SVETLA STOILOVA-MCPHIE
• 金额: $ 2.45万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361087
• 关键词: Affect; Binding; Blood; Blood Coagulation Factor; Blood Platelets; Blood coagulation; Cells; Coagulants; Complex; Cryoelectron Microscopy; Electron Microscopy; Ensure; Equilibrium; Factor IXa; Factor VIII; Factor VIIIa; Factor Xa; Funding; Generations; Goals; Grant; Hemophilia A; Hemostatic function; Life; Lipids; Membrane; Molecular Conformation; Mutation; Nanotubes; National Center for Research Resources; Pathway interactions; Population; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Serine Protease; Source; Structure; Surface; Thrombin; Time; United States National Institutes of Health; cost; factor IXa-factor VIIIa; image reconstruction; intravenous administration; macromolecule; male

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Blood coagulation is ensured through equilibrium between pro- and anti-coagulant coagulation factors that interact with each other and cells. Factor VIII (FVIII) is a large multidomain protein (~280kDa), which in its active form, Factor VIIIa (FVIIIa) acts as a co-factor to the serine protease Factor IXa (FIXa) within the membrane-bound Tenase complex. Binding of FVIIIa to FIXa onto the platelet surface increases Factor Xa (FXa) and Thrombin generation more than 10^6 times. Mutations in FVIII result in mild to severe Haemophilia type A, a life-threatening blood condition affecting one in 5000 of the male population (Wacey et al., 1996). The sole cure for this condition is intravenous administration of FVIII, whose membrane-bound structure has been studied by Stoilova-McPhie using cryoEM. Our goal is to define the active conformation (structure) of the membrane-bound complex(es) of blood coagulation factors essential for the aniticoagulant pathways of blood hemostasis. Our approach is to organize them helically (onto) a lipid nanotube and define (their) membrane-bound structure (combining) Cryo-EM and image reconstruction.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 通过促凝和抗凝凝血因子之间的平衡来确保血液凝固，这些凝血因子彼此之间以及细胞之间相互作用。因子 VIII (FVIII) 是一种大型多结构域蛋白 (~280kDa)，在其活性形式下，因子 VIIIa (FVIIIa) 在膜结合 Tenase 复合物中充当丝氨酸蛋白酶因子 IXa (FIXa) 的辅助因子。 FVIIIa 与 FIXa 结合到血小板表面可将 Xa 因子 (FXa) 和凝血酶的生成增加 10^6 倍以上。 FVIII 突变会导致轻度至重度 A 型血友病，这是一种危及生命的血液病，影响着五千分之一的男性人口（Wacey 等，1996）。这种情况的唯一治疗方法是静脉注射 FVIII，Stoilova-McPhie 使用冷冻电镜研究了 FVIII 的膜结合结构。 我们的目标是定义对于血液止血的抗凝血途径至关重要的凝血因子的膜结合复合物的活性构象（结构）。我们的方法是将它们螺旋地组织在脂质纳米管上，并定义（它们的）膜结合结构（结合）冷冻电镜和图像重建。