PATHOBIOLOGY OF HUMAN FACTOR IX: STRUCTURE AND FUNCTION

人类因子 IX 的病理学：结构和功能

• 批准号: 3342242
• 负责人: Arthur Rumford Thompson
• 金额: $ 11.71万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1989-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3342242
• 关键词: blood coagulation tests; calcium; chemical cleavage; chemical structure function; coagulation factor IX; coagulation factor VIII; coagulation factor X; cofactor; congenital blood protein disorder; endonuclease; gene expression; hemophilia B; hemostasis; human tissue; immunochemistry; immunologic techniques; molecular site; monoclonal antibody; nucleic acid sequence; pathologic process; phospholipids; platelets; proteolysis; thrombosis; vascular endothelium

Factor IX protein, although present in a very low concentration in plasma, is essential for hemostasis. Patients with congenital deficiency of factor IX, hemophilia B, have a bleeding disorder with a prevalence of 5 per 100,000 males. These patients require an inordinate supply of donor blood products to control their bleeding and thus lead nearly normal lives. Acquired factor IX defects are uncommon by themselves but accompany the depression of other vitamin K-dependent clotting factors in liver disease and in patients on oral anticoagulants. Management of bleeding in the acquired defects is much more difficult. In order to function in clotting, factor IX must be converted to an active form, factor IXa. Just how this occurs either normally or pathologically is poorly understood as are the means of limiting its activity. Since factor IX activation is one of the initial steps of a long series of biochemical reactions which lead to clotting, it provides excellent potential for either setting off or controlling the very common disorders of thrombosis. A greater understanding of interactions between this plasma protein, blood platelets (the clotting cells) and the innner walls of the blood vessels is needed. It is proposed that elucidating the functional abnormalities and structural bases of hemophilic (abnormal) factor IX proteins will provide insights into the role of this clotting protein in normal blood clotting and thrombosis. Antibody techniques to purify abnormal factor IX proteins from patients' plasmas are being developed. The abnormal factor IX proteins will be labeled with a trace of radioactivity and studied by sensitive immunochemical methods. Characterization will include micro-screening tests for: 1) their ability to be converted from an inactive precursor to the active form, 2) their ability to be broken down by certain enzymes, 3) their functional properties as enzymes and 4) their interactions with cofactors. We will also be able to assess for unstable variants which are cleared more rapidly than normal from the circulation. Studies of hemophilic factor IX genes will be used to determine what is wrong with the structure of a given hemophilic factor IX protein by identifying the abnormality in the genetic code.

因子 IX 蛋白虽然在血浆中的浓度非常低， 对于止血至关重要。 先天性因子缺乏症患者 IX，血友病 B，患有出血性疾病，患病率为 5/ 100,000 名男性。 这些患者需要过量的献血供应 控制出血的产品，从而过上近乎正常的生活。 获得性因子 IX 缺陷本身并不常见，但伴随着 肝脏疾病中其他维生素 K 依赖性凝血因子的抑制 以及服用口服抗凝剂的患者。 出血的处理 获得性缺陷要困难得多。 为了发挥凝血功能，因子 IX 必须转化为活性物质 形式，因子IXa。 这到底是如何在正常或病理情况下发生的 人们对限制其活动的手段知之甚少。 自从 因子 IX 激活是一系列的初始步骤之一 导致凝血的生化反应，它提供了极好的 引发或控制非常常见疾病的潜力 血栓形成。 更好地了解等离子体之间的相互作用 蛋白质、血小板（凝血细胞）和血管内壁 需要血管。 建议阐明功能异常和结构异常 血友病（异常）因子 IX 蛋白的基础将提供见解 了解这种凝血蛋白在正常血液凝固中的作用以及 血栓形成。 纯化异常因子 IX 蛋白的抗体技术 患者血浆正在开发中。 异常的IX因子蛋白 将被标记有微量放射性并由敏感的人进行研究 免疫化学方法。 表征将包括微筛选 测试：1）它们从非活性前体转化为 活性形式，2) 它们被某些酶分解的能力，3) 它们作为酶的功能特性以及 4) 它们与 辅助因子。 我们还能够评估不稳定的变体，这些变体是 从循环中清除的速度比正常情况更快。 研究 血友病因子 IX 基因将用于确定出现了什么问题 通过鉴定给定血友病因子 IX 蛋白的结构 遗传密码异常。