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: 8147399
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8147399
• 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

PROJECT SUMMARY (See instructions): 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.

项目摘要（请参阅说明）： 这项研究的长期目标是了解关键酶之间的控制相互作用 血液凝血系统。希望从这些研究中得出的信息将有助于改善 不仅为患有出血疾病的人，还为受到更广泛健康影响的人的治疗 问题，血栓形成。 为了实现这些目标，研究将包括以下具体研究目的：1）确定任何 与维生素K环氧化物还原酶合作的辅助因子或其他配件蛋白在产生维生素K氢喹酮时； 2）研究控制因子IX与胶原蛋白IV的相互作用及其在凝结中的作用； 3）表征药理学剂量因子Vila的机制 恢复止血。 这些目标将通过使用从基本生物化学和分子生物学到动物模型的多方面方法来实现。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环还原酶与其他细胞蛋白的相互作用。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VII因子VII 将在各种模型系统中进行评估的变体，包括基于细胞的凝血模型和动物模型，包括因子IX缺乏小鼠和小鼠与不结合胶原蛋白IV的因子IX。这些分子的体内效应将通过浸润显微镜评估。