Molecular Regulation of Arterial Thrombosis

描述（由申请人提供）：该项目的总体目标是了解组织因子通路在血管稳态中的复杂调节作用。当内皮破坏或损伤导致内皮下促凝剂（包括组织因子（TF））暴露于流动的血液并被激活时，动脉血栓形成就开始了。我们重点研究了组织因子途径抑制剂（TFPI）作为TF的主要生理抑制剂。内皮管腔表面的局部活性TFPI提供了一个处于不受干扰状态的非血栓形成表面。TFPI是一种kunitz型丝氨酸蛋白酶抑制剂，通过与tf因子Vila（通过K1结构域）和因子Xa（通过K2结构域）结合形成抑制复合物，从而独特地改变体内凝血级联反应。然而，如果局部TFPI水平不足以抑制局部TF活性，血栓形成仍会继续。TFPI，通过提出的直接作用和间接通过其抗凝特性，也影响血管结构。我们的目标是确定内皮在这一过程中的作用。局部活跃的TFPI可能来源于血管细胞或循环。

DESCRIPTION (provided by applicant): The overall goal of this project is to understand the complex regulatory role of the tissue factor pathway in vascular homeostasis. Arterial thrombosis is initiated when endothelial disruption or injury leads to exposure and activation of subendothelial procoagulants, including tissue factor (TF), to flowing blood. We have focused on tissue factor pathway inhibitor (TFPI) as the major physiologic inhibitor of TF. Locally active TFPI at the luminal surface of endothelium provides a nonthrombogenic surface in the unperturbed state. TFPI, a Kunitz-type serine-protease inhibitor, uniquely modifies the coagulation cascade in vivo by binding to TF-factor Vila (via the K1 domain) and factor Xa (via the K2 domain) forming an inhibitory complex which dampens further coagulation. However, if local levels of TFPI are not adequate to dampen local TF activity, thrombosis continues. TFPI, via proposed direct effects and indirectly via its anticoagulant properties, also influences vascular structure. Our objective is to define the role of the endothelium in this process. Locally active TFPI may be derived from vascular cells or from the circulation. Endothelial cells may play at least two roles in these processes: as a site of TFPI action and as an accessible source of local and circulating forms. These functions may vary in distinct vascular beds. Recent clinical studies indicate an association between low circulating TFPI levels and increased vascular risk. The focus of this proposal is to delineate the role of endothelial-derived TFPI in regulating the homeostatic balance between TF and TFPI and its resultant effects on macro- and micro-vascular structure, function and thrombosis in multiple vascular beds. Our underlying hypothesis is that endothelial production of TFPI regulates circulating and local TFPI levels which modulate micro- and macro-vascular function and thrombosis during development and in adults. Three specific aims are proposed. Specific Aim 1: To determine the effects of endothelial-specific gene deletion of TFPI on murine development and hemostasis. Specific Aim 2: To define the role of endothelial-derived TFPI on vascular thrombosis. Specific Aim 3: To define the role of endothelial-derived TFPI on vascular remodeling including angiogenesis.