PROTEIN Z DEPENDENT PROTEINASE INHIBITOR

描述（由申请人提供）：蛋白Z （PZ）是一种维生素k依赖性血浆蛋白，作为PZ依赖性蛋白酶抑制剂（ZPI）抑制Xa因子的辅助因子。ZPI是蛋白酶抑制剂serpin超家族的成员，不仅以PZ、Ca2+和磷脂依赖的方式抑制Xa因子，而且直接抑制凝血因子XIa。小鼠模型的证据表明，PZ/ZPI系统在凝血调节中起着重要的生理作用。本提案的目标是：1)仔细表征磷脂表面（包括血小板）在PZ/ZPI抗凝功能中的作用；2)确定PZ和ZPI抑制Xa和XIa因子的分子机制；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发现的表达并探索其生理意义。4)进一步明确PZ和ZPI缺乏与血栓性疾病的关系，重点关注抗磷脂综合征、动脉粥样硬化以及获得性PZ/ZPI缺乏发展的潜在机制。这项工作将利用生化技术、重组生产、改变形式的蛋白质进行结构/功能分析，以及小鼠模型来确定PZ/ZPI系统的病理生理相关性。该提案的目标将提供目前缺乏的重要和全面的信息，这将增强我们对这一先前未确定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依赖性蛋白酶抑制剂（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。本研究的目的是更好地表征PZ和ZPI的表达和代谢，确定它们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的凝血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.