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: 10606626
• 负责人: Laurent Olivier Mosnier
• 金额: $ 66.43万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606626
• 关键词: AMD3100; Adult; Antibodies; Antifibrinolytic Agents; Arthritis; Attenuated; Automobile Driving; Basic Science; Binding; Blood Coagulation Factor; Blood Vessels; CXCR; CXCR4 gene; Carboxypeptidase; Carboxypeptidase U; 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; Life; Mediating; Modeling; Molecular; Mus; Mutagenesis; Neuropilins; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Physiological; Plasma; Population; Predisposition; Prevention; Productivity; Prophylactic treatment; Protein Isoforms; Receptor Signaling; Regenerative pathway; Regulation; Role; Severities; Signal Transduction; Stromal Cell-Derived Factor 1; 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; knowledge translation; 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).

项目摘要/摘要 本申请寻求为血浆前羧基肽酶B定义新的生理功能，凝血酶- 可激活纤溶抑制物(TAFI)。激活的TAFI(TafiA)是一种多功能的羧肽酶，具有 在调节纤溶、补体和炎症途径中的各种调控功能。有缺陷的 血友病患者血浆中TAFI的体外激活很早以前就被认识到了，但我们直到最近才发现 能够证明TAFI在血友病小鼠体内的激活也是有缺陷的。因此，血友病，这是 凝血因子VIII或IX的遗传缺陷提供了一种临床上相关的条件来改善我们的 理解Tafi缺乏的(病理)生理后果，因为Tafi是一种遗传缺陷 在人类身上还没有被发现。血友病患者出血的特点是显著的 负重关节反复和永久性关节内出血的易感性 虚弱的血友病关节病。世界上大多数血友病人口无法获得 严格供应用于预防性治疗的凝血因子产品，因此血友病关节病 并将在未来几代人中在成人血友病人群中高度流行。此外， 在晚年开始预防凝血因子并不能减少现有的血友病关节病，这表明 对血友病关节病(HJD)发病机制的新认识，这可能导致其他治疗选择 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理性关节 其特征是由于过度的血管重塑导致明显的血管异常。我们的工作已经完成 发现TAFI的激活缺陷导致了与HJD相关的小鼠血管异常 关节出血。此外，由于TAFI功能的丧失，出血后关节内的血管变化如下 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对 塔菲参与其中。拟议的研究将测试一个全面的概念模型，旨在获得基本的 以及为血友病和关节病患者造福的翻译知识。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的减退 1α(sdf-1α/cxcl12))活性作为血管异常发生的驱动力 HJD。三个具体目标将指导我们的实验。关于TAFI缺失如何发挥作用的新认识 对HJD的贡献将是目标1的重点。对目标2的研究将测试Tafia减弱血管内皮生长因子-A的能力 活动以及这与HJD有何关系。目标3的重点是调节sdf-1α活性的tafia和 靶向SDF-1α信号受体预防和逆转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可以是 转化为血友病关节病患者的血管治疗，包括工程TAFI变体 (目标1)、抗体(目标2)或小分子(目标3)。