BLOOD COAGULATION FACTOR

凝血因子

• 批准号: 8168563
• 负责人: SVETLA STOILOVA-MCPHIE
• 金额: $ 2.15万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168563
• 关键词: Affect; Binding; Blood; Blood Coagulation Factor; Blood Platelets; Blood coagulation; Cells; Coagulants; Complex; Computer Retrieval of Information on Scientific Projects Database; Cryoelectron Microscopy; Crystallization; Electron Microscopy; Ensure; Environment; Equilibrium; Factor IXa; Factor VIII; Factor VIIIa; Factor Va; Factor Xa; Funding; Generations; Goals; Grant; Hemophilia A; Institution; Life; Lipids; Membrane; Methods; Mutation; Nanotubes; Population; Proteins; Research; Research Personnel; Resources; Serine Protease; Source; Structure; Surface; Thrombin; Time; United States National Institutes of Health; design; factor IXa-factor VIIIa; intravenous administration; male; protein structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 electron microscopy (Parmenter and Stoilova-McPhie, 2008; Stoilova-McPhie et al., 2008). CryoEM is a unique method capable of defining the structure of proteins in their native environment. For this purpose we have designed lipid nanotubes (LNT) for helical crystallization of FVIII and its complexes, allowing its membrane-bond structure to be resolved by Cryo-EM. Defining the structure of membrane-bound blood coagulation Factor Va and Factor VIIIa attached to lipid nanotubes by Cryo-electron microscopy is the primary goal of this project.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 血液凝结是通过彼此相互作用和细胞相互作用的促凝结因子和抗凝血凝结因子之间的平衡来确保的。 VIII因子（FVIII）是一种大型多域蛋白（〜280KDA），其活性形式为VIIIA（FVIIIA），在膜结合结合的预性预性预性预性预酶络合物中充当了丝氨酸蛋白酶IXA（FIXA）的共同因素。 FVIIIA与固定剂对血小板表面的结合增加了因子Xa（FXA）和凝血酶生成的10^6倍以上。 FVIII的突变导致轻度至重度A型血友病，这是一种威胁生命的血液状况，影响了5000名男子中的一个（Wacey等，1996）。这种情况的唯一治愈方法是FVIII的静脉内给药，使用电子显微镜通过Stoilova-McPhie研究了膜结构的结构（Parmenter和Stoilova-McPhie，2008; Stoilova-McPhie et al。，2008）。 冷冻物是一种能够在其本地环境中定义蛋白质结构的独特方法。为此，我们为FVIII及其复合物的螺旋结晶设计了脂质纳米管（LNT），从而可以通过冷冻EM解决其膜键结构。 通过冷冻电子显微镜定义膜结合血液凝结因子VA的结构和与脂质纳米管相连的VIIIA的结构是该项目的主要目标。