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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 通过相互作用和与细胞相互作用的促凝血因子和抗凝凝血因子之间的平衡来确保血液凝固。因子VIII（FVIII）是一种大的多结构域蛋白（~ 280 kDa），其活性形式为因子VIIIa（FVIIIa），在膜结合Tenase复合物内作为丝氨酸蛋白酶因子IXa（FIXa）的辅因子。 FVIIIa与血小板表面的FIXa结合可使Xa因子（FXa）和凝血酶生成增加10^6倍以上。 FVIII中的突变导致轻度至重度A型血友病，这是一种危及生命的血液疾病，影响5000名男性人群中的一人（Wacey等人，1996年）的报告。这种情况的唯一治疗方法是静脉注射FVIII，其膜结合结构已由Stoilova-McPhie使用cryoEM研究。 我们的目标是确定凝血因子的膜结合复合物的活性构象（结构），这些凝血因子对血液止血的抗凝途径至关重要。我们的方法是将它们螺旋状地组织到脂质纳米管上，并结合Cryo-EM和图像重建来定义它们的膜结合结构。