Novel functions of Thrombin Activatable Fibrinolysis Inhibitor (TAFI)

凝血酶激活纤溶抑制剂（TAFI）的新功能

• 批准号: 10378545
• 负责人: Laurent Olivier Mosnier
• 金额: $ 65.14万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378545
• 关键词: AMD3100; Adult; Antibodies; Antifibrinolytic Agents; Arthritis; Attenuated; Automobile Driving; Basic Science; Binding; Blood Coagulation Factor; Blood Vessels; CXCL12 gene; CXCR4 gene; Carboxypeptidase; Carboxypeptidase U; Cells; Clinical; Coagulation Factor Deficiency; Coagulation Process; Complement; Complex; Data; Development; Engineering; Excision; Factor IX; Factor VIII; Family member; Fibrin; Functional disorder; Generations; Genetic; Goals; Hemophilia A; Hemophilic Arthritis; Hemorrhage; Hemostatic Agents; Human; Hypoxia; Impairment; In Vitro; Inflammatory; Injury; Investigation; Joints; Knowledge; Lead; Life; Mediating; Modeling; Molecular; Mus; Mutagenesis; Neuropilins; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Physiological; Plasma; Population; Predisposition; Prevention; Prophylactic treatment; Protein Isoforms; Receptor Signaling; Regenerative pathway; Regulation; Role; Severities; Signal Transduction; Stromal Cells; Structure; Testing; Therapeutic; Translating; Translational Research; VEGFA gene; Variant; Vascular Diseases; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vascular regeneration; Vascular remodeling; Weight-Bearing state; Work; antagonist; arginylarginine; arthropathies; attenuation; clinically relevant; driving force; improved; improved outcome; in vivo; mouse model; neovascular; novel; prevent; regenerative repair; response; small molecule; vascular abnormality; vascular contributions

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).

项目概要/摘要 本申请旨在定义血浆原羧肽酶 B、凝血酶的新生理功能 可激活的纤溶抑制剂（TAFI）。活化的 TAFI (TAFIa) 是一种多功能羧肽酶，具有 纤溶、补体和炎症途径调节中的各种调控功能。有缺陷的 很久以前就已经认识到血友病血浆中 TAFI 的体外激活，但我们直到最近才发现 能够证明血友病小鼠体内的 TAFI 激活也是有缺陷的。因此，血友病是 凝血因子 VIII 或 IX 的遗传缺陷，提供了临床相关的条件来改善我们的 由于 TAFI 遗传缺陷，了解 TAFI 缺陷的（病理）生理后果 在人类中尚未发现。血友病患者出血的特点是显着 负重关节易发生反复和持续的关节内出血，并进展为 衰弱性血友病关节病。世界上大多数血友病患者无法获得治疗 用于预防性治疗的凝血因子产品的严格供应，导致血友病性关节病 并且在未来的许多代人中，成人血友病人群中仍将高度流行。此外， 晚年开始凝血因子预防并不能减少现有的血友病关节病，这表明 关于血友病关节病（HJD）机制的新知识，可能会带来更多的治疗选择 对于血友病和关节病患者来说，都是迫切需要的。血友病患者的关节病变 其特征是由于过度的血管重塑而导致明显的血管异常。我们的工作有 发现 TAFI 激活缺陷会导致小鼠中与 HJD 相关的血管异常 关节出血。此外，由于TAFI功能丧失，出血后关节内的血管变化是 不能用 TAFI 抗纤维蛋白溶解活性的丧失来解释，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 和转化知识，造福血友病和关节病患者。我们的新颖假设 重点关注血管内皮生长因子A（VEGF-A）和基质细胞衍生因子的衰减损失- TAFIa 的 1α (SDF-1α/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 功能丧失如何发挥作用的新知识 对 HJD 的贡献将是目标 1 的重点。目标 2 的研究将测试 TAFIa 减弱 VEGF-A 的能力 活动以及这与 HJD 的关系。目标 3 重点关注 TAFIa 和 SDF-1α 活性的调节 靶向 SDF-1α 信号受体可以在多大程度上预防和逆转 HJD。一个非常重要的前提 是关于 HJD 血管异常机制的基本知识可以 转化为血友病关节病患者的血管治疗，包括工程化 TAFI 变体 （目标 1）、抗体（目标 2）或小分子（目标 3）。