Factor VIIa interaction with Endothelial Cell Protein C Receptor

因子 VIIa 与内皮细胞蛋白 C 受体的相互作用

基本信息

批准号：
9328143
负责人：
Vijaya Mohan Rao Lella
金额：
$ 36.78万
依托单位：
UNIVERSITY OF TEXAS HLTH CTR AT TYLER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9328143
关键词：
Acute Adult Anti-Inflammatory Agents Anti-inflammatory Antibodies Anticoagulants Binding Biodistribution Biological Biological Models Blood Circulation Blood Coagulation Disorders Blood Coagulation Factor Blood Vessels Bypass Childhood Clinical Treatment Coagulation Process Data Development Dimensions Down-Regulation Emergency Situation Endothelial Cells Endothelium Extravasation F8 gene Factor VIIa Factor Va Fc Receptor Funding Generations Hemophilia A Hemorrhage Hemostatic Agents Hemostatic function In Vitro Inflammation Injury Joints Knee Injuries Knowledge Laboratories Lead Ligands Ligation Mediating Mus Needles Outcome PAR-1 Receptor Pathway interactions Patients Pharmacology Phospholipids Play Positioning Attribute Prevention Prophylactic treatment Protein C Prothrombin Puncture procedure Recombinants Role Saphenous Vein Signal Transduction Site Testing Therapeutic Thrombin Thromboplastin Time Tissues Transgenic Mice Variant Work activated Protein C activated protein C receptor arthropathies base bone loss clinical efficacy cofactor cost cost effective design improved in vivo in vivo Model inhibitor/antagonist joint destruction joint injury novel novel therapeutics prevent prophylactic protective effect protein activation public health relevance receptor recombinant FVIIa

项目摘要

DESCRIPTION (provided by applicant): Recent studies showed that clotting factor FVIIa (FVIIa), which initiates the coagulation cascade upon binding to procoagulant cofactor tissue factor (TF) following vascular injury, also binds to anticoagulant cofactor endothelial cell protei C receptor (EPCR). EPCR plays a critical role in the protein C anticoagulant pathway by promoting the activation of protein C. EPCR also promotes activated protein C (APC)-induced cytoprotective signaling. Studies conducted in the last funding cycle revealed that FVIIa binding to EPCR on the endothelium facilitates the transport of FVII/FVIIa from the circulation to extravascular sites and FVIIa bound to EPCR activates the protease-activated receptor 1 (PAR1)-mediated cell signaling and provides the barrier protective effect. Pharmacological concentrations of rFVIIa were found to displace endogenous protein C from EPCR. rFVIIa is routinely used to treat hemophilia patients with inhibitory antibodies against FVIII and FIX. It is also being used as an emergency hemostatic agent in both pediatric and adult patients. Despite its widespread and successful use, the understanding of the mechanism of rFVIIa action in bleeding disorders is incomplete. A clear understanding of the mechanistic action of rFVIIa in therapy is essential to improve the clinical efficacy of rFVIIa, and to better manage patients and develop a new generation of FVIIa-based therapeutics. We hypothesize that pharmacological concentrations of rFVIIa compete with endogenous protein C for the limited EPCR sites on the endothelium, which diminishes EPCR-dependent APC generation, and thus the down-regulation of the APC anticoagulant pathway. The down-regulation of the APC anticoagulant pathway would enhance FVIIa-induced thrombin generation as factor Va is not readily inhibited by the reduced APC levels. We also hypothesize that EPCR-mediated FVIIa transport and FVIIa-EPCR-mediated barrier protective and anti-inflammatory effects play crucial roles in preventing the joint damage and bone loss in rFVIIa prophylaxis. The following aims will test the above hypotheses. Aim 1: Investigate the importance of FVIIa:EPCR interaction in the hemostatic effect of rFVIIa in treating bleeding disorders and elucidate its mode of action; Aim 2: Characterize FVIIa bio-distribution and tissue retention in prophylaxis and evaluate the contribution of FVIIa-EPCR-mediated hemostatic, barrier protective and anti-inflammatory effects to the prophylactic effect of preventing hemophilic arthropathy; and Aim 3: Elucidate the mechanism by which EPCR ligation with EPCR mAb, in the absence of rFVIIa treatment, provides the vascular barrier protective effect in hemophilia. To perform these studies, we will generate novel mFVIIa variants and unique transgenic mice and employ saphenous vein bleeding, the needle puncture knee injury, and VEGF-and LPS- induced vascular leakage model systems. The outcome of the proposed studies will introduce a paradigm shift in our understanding of how the pharmacological concentration of rFVIIa provides the hemostatic effect in hemophilia patients and patient with other bleeding disorders.

描述（申请人提供）：最近的研究表明，凝血因子 FVIIa (FVIIa) 在血管损伤后与促凝血辅因子组织因子 (TF) 结合后启动凝血级联，也与抗凝血辅因子内皮细胞蛋白 C 受体 (EPCR) 结合EPCR 通过促进蛋白 C 的激活，在蛋白 C 抗凝途径中发挥关键作用。EPCR 还促进激活的蛋白。 C (APC) 诱导的细胞保护信号传导在上一个资助周期中进行的研究表明，FVIIa 与内皮上的 EPCR 结合促进 FVII/FVIIa 从循环转运至血管外位点，并且与 EPCR 结合的 FVIIa 激活蛋白酶激活受体 1。 (PAR1) 介导的细胞信号传导并提供屏障保护作用，发现 rFVIIa 的药理学浓度可取代 EPCR 中的内源性蛋白 C。 rFVIIa 通常用于治疗具有 FVIII 和 FIX 抑制性抗体的血友病患者。尽管 rFVIIa 已被广泛且成功地使用，但它也被用作儿科和成人患者的紧急止血剂，但对 rFVIIa 在出血性疾病中的作用机制的了解并不完整。提高 rFVIIa 的临床疗效，并更好地管理患者并开发新一代基于 FVIIa 的疗法。我们发现 rFVIIa 的药理学浓度与内源性蛋白 C 竞争有限的 EPCR 位点。 APC 抗凝途径的下调将增强 FVIIa 诱导的凝血酶生成，因为因子 Va 不易被减少的抑制。我们还提高了 EPCR 介导的 FVIIa 转运和 FVIIa-EPCR 介导的屏障保护和抗炎作用在预防关节损伤和骨质流失方面发挥着至关重要的作用。 rFVIIa 预防。目标 1：研究 FVIIa：EPCR 相互作用在 rFVIIa 治疗出血性疾病的止血作用中的重要性，并阐明其作用模式；目标 2：表征 FVIIa 的生物分布和组织。保留预防措施并评估 FVIIa-EPCR 介导的止血、屏障保护和抗炎作用对治疗的贡献预防血友病关节病的预防作用；目标 3：阐明在没有 rFVIIa 治疗的情况下，EPCR 与 EPCR mAb 连接对血友病提供血管屏障保护作用的机制。独特的转基因小鼠并采用隐静脉出血、针刺膝损伤以及 VEGF 和 LPS 诱导的血管渗漏模型系统。拟议研究中的一部分将在我们对 rFVIIa 的逻辑药理学浓度如何为血友病患者和患有其他出血性疾病的患者提供止血作用的理解上带来范式转变。