INTERACTIONS CONTROLLING VITAMIN K-DEPENDENT COAGULATION

控制维生素 K 依赖性凝血的相互作用

• 批准号: 7667046
• 负责人: DARREL W STAFFORD
• 金额: $ 43.13万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667046
• 关键词: Affect; Animal Model; Binding; Biochemical; Biochemistry; Biological Models; Blood Clot; Blood Coagulation Factor VII; Blood coagulation; Cause of Death; Cells; Coagulation Process; Collagen Type IV; Country; Disease; Dose; Elements; Enzymes; Factor IX; Goals; Health; Hemorrhage; Hemostatic function; Hydroquinones; Individual; Instruction; Lead; Methods; Modeling; Molecular Biology; Mus; Myocardial Infarction; Proteins; Research; Role; Stroke; System; Therapeutic; Thrombosis; United States; Variant; Vitamin K; Vitamins; base; cofactor; hydroquinone; improved; in vivo; intravital microscopy; tissue culture; vitamin K epoxide reductase

The long-term goal of this research is to understand the controlling interactions among key enzymes in the blood coagulation system. It is hoped that information derived from these studies will help improve treatments for, not only individuals with bleeding disorders, but also for those affected by the broader health problem, thrombosis. To accomplish these goals the studies will include the following specific research aims: 1) identify any cofactors or other accessory proteins that collaborate with vitamin K epoxide reductase in producing vitamin K hydroquinone; 2) investigate the structural elements controlling factor IX interactions with collagen IV and its role in coagulation; and 3) characterize the mechanism by which pharmacologic doses of factor Vila restore hemostasis. These aims will be achieved by using multifaceted approaches ranging from basic biochemistry and molecular biology to animal models. Studies will employ molecular biology, tissue culture, and biochemical methods to investigate the interaction of vitamin K epoxide reductase with other cellular proteins. Similar molecular biology and tissue culture methods will be used to create coagulation factor IX and factor VII variants which will be evaluated in a variety of model systems including a cell-based coagulation model and animal models including factor IX deficient mice and mice with factor IX that does not bind collagen IV. In vivo effects of these molecules will be evaluated by intravital microscopy.

这项研究的长期目标是了解凝血系统中关键酶之间的控制相互作用。希望从这些研究中获得的信息不仅有助于改善对出血性疾病患者的治疗，而且还有助于改善对受更广泛的健康问题（血栓形成）影响的患者的治疗。 为了实现这些目标，研究将包括以下具体研究目标：1）确定与维生素 K 环氧化物还原酶协同生产维生素 K 对苯二酚的任何辅因子或其他辅助蛋白； 2）研究控制因子IX与胶原IV相互作用的结构元件及其在凝血中的作用； 3)表征药物剂量的因子VIIa恢复止血的机制。 这些目标将通过使用多方面的方法来实现，从基础生物化学到 分子生物学到动物模型。研究将采用分子生物学、组织培养和生化方法来研究维生素 K 环氧化物还原酶与其他细胞蛋白质的相互作用。类似的分子生物学和组织培养方法将用于创建凝血因子 IX 和因子 VII 变体，这些变体将在各种模型系统中进行评估，包括基于细胞的凝血模型和动物模型，包括因子 IX 缺陷小鼠和因子 IX 小鼠不结合 IV 型胶原蛋白。这些分子的体内作用将通过活体显微镜进行评估。