STRUCTURE & MOLECULAR BIOLOGY OF THE PROTEIN S GENE

蛋白S是调节止血的关键组分。 蛋白质S是活化蛋白质C的辅因子， 负责降解的两个蛋白质元素的 凝血途径 因此，蛋白S通过 蛋白C的作用下调血液凝固过程。 缺乏功能性蛋白S的个体，无论是因为 遗传或环境获得的原因，风险较高 血栓性疾病 症状通常 与蛋白S缺乏相关的包括血栓性静脉炎， 深静脉血栓和肺栓塞 在目前 蛋白S缺乏症的遗传基础及其与 血栓形成未知。 拟议的长期目标 研究的目的是了解蛋白S缺乏症的遗传基础 和血栓形成。 这将在一定程度上通过 拟议的研究，旨在更好地了解 正常和异常蛋白S基因及其功能 蛋白质S产物的性质。 的具体方法 实现这些目标包括：a）克隆和表征（通过 限制性内切酶和DNA测序）的正常 人蛋白S基因及其与遗传学比较 蛋白S缺陷型个体，B）蛋白S缺陷型个体的染色体定位， 蛋白S基因的特异性杂交， 缺乏不同人类染色体的小鼠-人类细胞杂交体， c）定量细胞中蛋白S信使RNA水平 相信或怀疑参与止血， 止血调节因子的影响，和d）定点 蛋白S的诱变以解决结构/功能 关系，包括β-羟基天冬氨酸和 γ-羧基谷氨酸、凝血酶裂解和表皮 生长因子、前肽和蛋白S中的“Gla”结构域。 的 结果可能最终导致改进的诊断方法， 蛋白S缺乏和/或患有 血栓性疾病

Protein S is a key component for the regulation of hemostasis. Protein S serves as a cofactor for activated protein C, an enzyme responsible for the degradation of two protein elements of the blood coagulation pathway. Consequently, protein S through the action of protein C down-regulates the blood clotting process. Individuals deficient in functional protein S, either because of genetic or environmentally-acquired reasons, are at a higher risk of experiencing thrombotic disorders. Symptoms commonly associated with Protein S deficiency include thrombophlebitis, deep vein thrombosis, and pulmonary emboli. At the present time the genetic basis of protein S deficiency and its relationship to thrombosis are unknown. The long-term objective of the proposed research is to understand the genetic basis of protein S deficiency and thrombosis. This will be accomplished, in part, through the proposed studies, designed to provide a better understanding of the normal and abnormal protein S genes and the functional properties of the protein S products. Specific methods for achieving these goals include: a) cloning and characterization (by restriction endonuclease and DNA sequencing) of the normal human protein S gene and comparison to that from genetically protein S deficient individuals, b) chromosomal localization of the protein S gene by specific hybridization of protein S cDNA to mouse-human cell hybrids lacking different human chromosomes, c) quantitation of protein S messenger RNA levels in cells believed or suspected of participating in hemostasis and under the influence of hemostatic regulatory factors, and d) site-directed mutagenesis of protein S to address structure/function relationships, including the role of beta-hydroxyaspartic and gamma-carboxyglutamic acids, thrombin cleavage, and epidermal growth factor, propeptide and "Gla" domains in proteins S. The results may eventually lead to improved methods of diagnosis and therapy for patients having protein S deficiency and/or suffering from thrombotic disorders.