VITAMIN K-DEPENDENT PROTEINS IN BLOOD AND DEVELOPMENT

血液和发育中的维生素 K 依赖性蛋白质

• 批准号: 6056530
• 负责人: David A Roth
• 金额: $ 11.69万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6056530
• 关键词: blood coagulation; clotting factor; developmental genetics; embryo /fetus drug adverse effect; embryo /fetus tissue /cell culture; embryogenesis; enzyme activity; gamma carboxyglutamate; gene expression; genetic regulatory element; genetic transcription; laboratory rat; mammalian embryology; nucleic acid sequence; posttranslational modifications; protein structure function; teratogens; transcription factor; transfection; vitamin K; warfarin

In what is the only known biological process dependent on vitamin K, the vitamin K-dependent lambda-glutamyl carboxylase catalyzes the posttranslational modification of glutamate to lambda-carboxyglutamate in the vitamin K-dependent proteins during their synthesis. This modification is essential for the biological activities of all known vitamin K-dependent proteins. Substrates of the carboxylase include several proteins involved in blood coagulation as well as bone matrix proteins and Gas6. Gas6, a cell cycle regulated protein is a ligand for receptor tyrosine kinases and has been implicated in the prevention of apoptosis of growth arrested cells. While we have previously focused our studies on the role of vitamin K-dependent carboxylation in hemostasis, we have recently demonstrated extrahepatic expression of the vitamin K-dependent carboxylase gene in adult and embryonic rat tissues, supporting the hypothesis that vitamin K has an important physiological role outside of blood coagulation. Warfarin, a potent vitamin K antagonist, is a widely used anticoagulant which indirectly inhibits the activity of the vitamin K-dependent carboxylase. Warfarin is also a teratogen. Human maternal exposure to warfarin during pregnancy is associated with developmental abnormalities in the fetus, the warfarin embryopathy, suggesting critical developmental functions for the carboxylase enzyme and its substrates. New data from our laboratory demonstrates temporal variations in tissue specific expression of vitamin K-dependent carboxylase mRNA in developing rat embryonic tissues, supporting the hypothesis that vitamin K-dependent carboxylation is a developmentally regulated posttranslational modification important for normal embryogenesis. In the current application, studies are proposed to clarify the role of vitamin K in development by examining the developmental and tissue specific expression of the vitamin K-dependent carboxylase in rat embryos. The regulation of vitamin K-dependent carboxylase gene transcription will be evaluated in vitro to study the factors that regulate vitamin K- dependent protein activity during development. An animal model of warfarin embryopathy will be developed, to direct future in vivo studies for testing the functions of carboxylase substrates in development of the normal embryo. Vitamin K-dependent carboxylation will serve as a model for other developmentally regulated posttranslational modifications of proteins important in fetal development.

在什么是唯一取决于维生素K的唯一已知的生物过程中， 维生素K依赖性的lambda-glutamyl羧化酶催化 将谷氨酸对lambda-羧基谷氨酸谷氨酸的翻译后修饰 在维生素K依赖性蛋白合成过程中。这 修改对于所有已知的生物学活动至关重要 维生素K依赖性蛋白。羧化酶的底物包括 几种参与血液凝结和骨基质的蛋白质 蛋白质和气6。 GAS6，细胞周期调节蛋白是一种配体 受体酪氨酸激酶与预防有关 生长停滞细胞的凋亡。虽然我们以前专注于 我们对维生素K依赖性羧化作用的研究 止血，我们最近证明了 成年和胚胎大鼠中的维生素K依赖性羧化酶基因 组织，支持维生素K具有重要的假设 血液凝结以外的生理作用。华法林，有效 维生素K拮抗剂是一种广泛使用的抗凝剂，间接 抑制维生素K依赖性羧化酶的活性。华法林 也是致病。人类母亲接触华法林 怀孕与胎儿发育异常有关， 华法林的胚胎病，提出关键的发展功能 用于羧化酶及其底物。来自我们的新数据 实验室表明组织特异性的时间变化 维生素K依赖性羧化酶mRNA在发育中的大鼠中的表达 胚胎组织，支持维生素K依赖性的假设 羧化是一种受发展的翻译后的 修饰对于正常的胚胎发生很重要。在电流中 提出了应用研究以阐明维生素K在 通过检查发育和组织特异性 维生素K依赖性羧化酶在大鼠胚胎中的表达。这 维生素K依赖性羧化酶基因转录的调节 在体外评估以研究调节维生素K-的因素 发育过程中依赖性蛋白质活性。动物模型 将开发华法林的胚胎病，以指导Vivo的未来 测试羧化酶底物在中的功能的研究 正常胚胎的发展。维生素K依赖性羧化 将作为其他受发展监管的模型 在胎儿中重要的蛋白质翻译后修饰 发展。