Novel functions of Thrombin Activatable Fibrinolysis Inhibitor (TAFI)

项目总结/摘要 本申请试图定义血浆羧肽酶原B，凝血酶-β-羧肽酶的新的生理功能。 活化纤维蛋白溶解抑制剂（TAFI）。活化的TAFI（TAFIa）是一种多功能羧肽酶， 在纤维蛋白溶解、补体和炎症途径的调节中的各种控制功能。缺陷 体外血友病血浆中TAFI的激活很久以前就被认识到了，但我们只是最近才被 能够证明血友病小鼠体内的TAFI活化也是有缺陷的。因此，血友病， 凝血因子VIII或IX的遗传缺陷，提供了临床相关的条件，以改善我们的 了解TAFI缺乏的（病理）生理后果，因为TAFI的遗传缺陷 血友病患者的出血特点是有一个显著的 在负重关节中反复和持续的关节内出血的易感性， 使人衰弱的血友病性关节病世界上大多数血友病患者无法获得 严格供应用于预防性治疗的凝血因子产品， 并将在未来的许多代人中在成人血友病人群中保持高度流行。此外，委员会认为， 在以后的生活中开始凝血因子预防并不能减少现有的血友病性关节病，这表明， 血友病性关节病（HJD）机制的新知识，可能导致额外的治疗选择 对于血友病和关节病患者来说，是急需的。血友病患者的关节病变 其特征在于由于过度的血管重塑而导致的显著的血管异常。我们的工作 发现TAFI的缺陷激活驱动了小鼠中与HJD相关的血管异常， 关节出血此外，由于TAFI功能丧失而出血后关节中的血管变化是 不能用TAFI的抗纤溶活性的丧失来解释，这表明其他机制和底物 TAFI参与其中。拟议的研究将测试一个全面的概念模型，旨在获得基本的 和翻译知识，以造福血友病和关节病患者。我们的新假设 关注血管内皮生长因子A（VEGF-A）和基质细胞衍生因子- 1 α（SDF-1 α/CXCL12））活性作为血管异常发展背后的驱动力， HJD。三个具体目标将指导我们的实验。关于TAFI功能丧失的新知识 对HJD的贡献将是目标1的重点。Aim 2的研究将测试TAFIa减弱VEGF-A的能力 活动以及与HJD的关系。目的3关注TAFIa对SDF-1 α活性的调节， 靶向SDF-1 α信号受体可以预防和逆转HJD的程度。一个非常重要的前提 关于HJD血管异常机制的基本知识， 转化为血友病性关节病患者的血管治疗，包括工程TAFI变体 (Aim 1）、抗体（Aim 2）或小分子（Aim 3）。

Project Summary/Abstract This application seeks to define new physiological functions for the plasma procarboxypeptidase B, Thrombin- Activatable Fibrinolysis Inhibitor (TAFI). Activated TAFI (TAFIa) is a multifunctional carboxypeptidase with various governing functions in the regulation of fibrinolytic, complement, and inflammatory pathways. Defective activation of TAFI in hemophilia plasma in vitro has been recognized long ago, but we have only recently been able to demonstrate that TAFI activation in hemophilia mice in vivo is also defective. Thus, hemophilia, which is a genetic deficiency of coagulation factor VIII or IX, provides a clinically relevant condition to improve our understanding of the (patho)physiological consequences of TAFI deficiency, since a genetic deficiency of TAFI in humans has not yet been found. Bleeding in patients with hemophilia is characterized by a striking susceptibility for repeated and perpetuated intra-articular bleeding in weight-bearing joints that progresses to debilitating hemophilic arthropathy. The majority of the world’s hemophilia population does not have access to a rigorous supply of clotting factor products for prophylactic treatment and as a result hemophilic arthropathy is and will remain highly prevalent in the adult hemophilia population for many generations to come. Furthermore, initiating clotting factor prophylaxis later in life does not diminish existing hemophilic arthropathy, indicating that new knowledge for mechanisms of hemophilic joint disease (HJD), that may lead to additional therapeutic options for patients with hemophilia and arthropathy, are urgently needed. Arthropathic joints in patients with hemophilia are characterized by pronounced vascular abnormalities due to excessive vascular remodeling. Our work has identified that the defective activation of TAFI drives the vascular abnormalities associated with HJD in mice after joint bleeding. Furthermore, the vascular changes in the joint after bleeding due to the loss of TAFI function are not explained by a loss of TAFI’s antifibrinolytic activity, suggesting that other mechanisms and substrates for TAFI are involved. The proposed studies will test a comprehensive conceptual model aimed at obtaining basic and translational knowledge for the benefit of patients with hemophilia and arthropathy. Our novel hypotheses focus on the loss of attenuation of vascular endothelial growth factor A (VEGF-A) and stromal cell-derived factor- 1α (SDF-1α/CXCL12)) activity by TAFIa as driving forces behind the development of vascular abnormalities in HJD. Three Specific Aims will guide our experimentation. New knowledge as to how a loss of TAFI function contributes to HJD will be the focus of Aim 1. Studies of Aim 2 will test the ability of TAFIa to attenuate VEGF-A activity and how this relates to HJD. Aim 3 is focused on the regulation of SDF-1α activity by TAFIa and the extent to which targeting SDF-1α signaling receptors can prevent and reverse HJD. A highly significant premise is that basic knowledge about the mechanisms responsible for the vascular abnormalities in HJD can be translated to vascular treatments for patients with hemophilic arthropathy, including engineered TAFI variants (Aim 1), antibodies (Aim 2), or small molecules (Aim 3).