PROTEIN Z DEPENDENT PROTEINASE INHIBITOR

描述(申请人提供)：蛋白Z(PZ)是一种维生素K依赖的血浆蛋白，是PZ依赖的蛋白酶抑制物(ZPI)抑制Xa因子的辅因子。ZPI是丝氨酸蛋白酶抑制剂超家族的成员，它不仅以PZ、钙和磷脂依赖的方式抑制Xa因子，而且还直接抑制凝血因子Xa。来自小鼠模型的证据表明，PZ/ZPI系统在凝血调节中发挥着重要的生理学作用。这项建议的目的是：1)详细描述磷脂表面(包括血小板)在PZ/ZPI抗凝功能中的作用，2)确定PZ和ZPI抑制因子Xa和Xia的分子机制，3)评估影响PZ和ZPI表达和血浆清除的过程，特别是表征它们最近在肾脏中的表达并探索其生理意义，以及4)进一步确定PZ与ZPI缺陷和血栓性疾病的关系，重点放在抗磷脂综合征、动脉粥样硬化和获得性PZ/ZPI缺陷发生的潜在机制上。这项工作将利用生化技术、生产用于结构/功能分析的重组、改变形式的蛋白质，以及小鼠模型来确定PZ/ZPI系统的病理生理学相关性。这项提案的目标将提供目前缺乏的重要和全面的信息，这些信息将加强我们对这一先前未知的凝血调节途径及其在人类疾病中的作用的理解。公共卫生相关性：蛋白Z(PZ)和蛋白Z依赖的蛋白酶抑制物(ZPI)是血浆蛋白，通过抑制两种凝血酶Xa和Xia的作用来调节凝血。该提案的目的是更好地描述PZ和ZPI的表达和代谢，确定它们潜在的抗凝作用的分子机制，并进一步确定它们在血栓栓塞性疾病中的作用。这项工作将提供重要的信息，将加强我们对PZ和ZPI对凝血的调节及其在人类血栓性疾病中的作用的理解。

DESCRIPTION (provided by applicant): Protein Z (PZ) is a vitamin K-dependent plasma protein that serves as a cofactor for the inhibition of factor Xa by PZ-dependent Protease Inhibitor (ZPI). ZPI is a member of the serpin superfamily of protease inhibitors and not only inhibits factor Xa in a PZ, Ca2+, and phospholipid-dependent manner, but also directly inhibits coagulation factor XIa. Evidence from mouse models demonstrates that the PZ/ZPI system plays a physiologic important role in the regulation of coagulation. The goals of this proposal are to 1) carefully characterize the role of the phospholipid surface (including that of platelets) in the anticoagulant function of PZ/ZPI, 2) determine the molecular mechanisms underlying the inhibition of factors Xa and XIa by PZ and ZPI, 3) evaluate the processes affecting the expression and plasma clearance of PZ and ZPI and, in particular, characterize their recently discovered expression in the kidney and explore its physiologic significance, and 4) further define the relationship between PZ and ZPI deficiency and thrombotic disease with an emphasis on the antiphospholipid syndrome, atherosclerosis, and potential mechanisms for the development of acquired PZ/ZPI deficiency. The work will utilize biochemical techniques, the production of recombinant, altered forms of the proteins for structure/function analysis, and mouse models to define the pathophysiologic relevance of the PZ/ZPI system. The goals of this proposal will provide important and comprehensive information, currently lacking, that will enhance our understanding of this previously unidentified pathway for the regulation of coagulation and its role in human disease. PUBLIC HEALTH RELEVANCE: Protein Z (PZ) and protein Z-dependent protease inhibitor (ZPI) are plasma proteins that regulate coagulation by inhibiting the action of two coagulation enzymes, factor Xa and factor XIa. The goals of this proposal are to better characterize the expression and metabolism of PZ and ZPI, determine the molecular mechanisms underlying their anticoagulant action, and further define their role in thromboembolic disease. The work will provide important information that will enhance our understanding of the regulation of coagulation by PZ and ZPI and its role in human thrombotic disease.