Factor XI in Thrombosis

血栓形成中的因子 XI

• 批准号: 8403680
• 负责人: David Gailani
• 金额: $ 37.05万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-06 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403680
• 关键词: Address; Affect; Antibodies; Attention; Bacterial Infections; Binding; Biological Assay; Blood; Blood Clot; Blood Platelets; Blood coagulation; Blood flow; Chimera organism; Coagulation Process; Conflict (Psychology); Coronary Arteriosclerosis; Data; Defect; Deposition; Disease; Disseminated Intravascular Coagulation; Enzyme Precursors; Factor IXa; Factor XI; Factor XII; Fibrin; Generations; Goals; Growth; Hemorrhage; Hemostatic function; High-Molecular-Weight Kininogen; Human; In Vitro; Inflammation; Injury; Mediating; Modeling; Molecular; Molecular Conformation; Mus; Oropharyngeal; Oryctolagus cuniculus; Papio; Pathologic; Pathologic Processes; Pathway interactions; Patients; Peptide Hydrolases; Phospholipids; Plasma; Plasma Proteins; Platelet Activation; Platelet aggregation; Play; Population; Prekallikrein; Primates; Process; Proteins; Recombinant Proteins; Resistance; Risk; Role; Sepsis; Structure; Surface; System; Techniques; Testing; Therapeutic; Thrombin; Thromboembolism; Thrombosis; Thrombus; Tissues; Transfection; Trypsin; Urinary tract; Variant; Vascular Graft; Venous; Vitamin K; Whole Blood; Wild Type Mouse; Work; base; cofactor; dimer; epidemiologic data; human data; in vivo; mortality; mouse model; mutant; novel; novel therapeutics; prevent; receptor; stem

PROJECT SUMMARY Factor (f) XI, the zymogen of the coagulation protease fXIa, serves a limited role in normal blood clotting (hemostasis), as fXI deficiency is associated with a relatively mild bleeding tendency. Despite this, work in baboons, rabbits, and mice, supported by human population data, strongly indicate that fXI makes important contributions to pathologic coagulation (thromboembolism). In classic coagulation models, fXI is converted to fXIa by activated fXII (fXIIa) in a process called contact activation, which also requires the proteins prekallikrein (PK) and high molecular weight kininogen (HK). The relevance of contact activation to hemostasis has been questioned, justifiably, as patients lacking fXII, PK or HK do not bleed abnormally. Based on this, in newer models of hemostasis fXI is activated through mechanisms distinct from contact activation. However, mice lacking fXII, similar to those lacking fXI, are resistant to thrombosis, suggesting contact activation (or a process similar to it) contributes to pathologic coagulation. While available epidemiologic data are conflicted regarding the importance of contact activation to thrombosis in humans, we noted that fXII contributes to fibrin formation and platelet aggregation in human blood in an ex vivo flow model. We hypothesize that fXII working through contact activation or a related process contributes to pathologic thrombus formation and stability in mice and primates, and that inhibiting this process can produce an anti-thrombotic effect. In Aim 1 of this proposal we will address the hypothesis that fXI must interact with platelets to contribute to thrombus formation by using transfection techniques that allow proteins to be transiently expressed in vivo. We will also investigate the possibility that fXIa can contribute to coagulation by processes distinct from those related to its classic function of activating factor IX. Studies in Aim 2 will investigate the interaction of fXI with fXIIa using chimeric and mutant recombinant proteins, conventional clotting assays, and whole blood flow models. We will also examine the importance of the fXI-HK interaction and the impact of PK deficiency on thrombus formation in mice. Previously we have shown that fXI deficiency confers a survival advantage in mice in models of bacterial infection. In Aim 3 we will compare the effects of fXI deficiency on survival, disseminated intravascular coagulation, and inflammation to those of deficiencies of fXII, HK, and PK in a model of polymicrobial sepsis in mice. We have demonstrated that inhibiting fXI with an antibody has a dramatic effect on the growth of platelet-rich thrombi in a baboon vascular graft thrombosis model. In Aim 4, we will compare the effects of fXI and fXII inhibition in this model to determine if fXII plays an important role in the growth of pathologic thrombi in primates. Results from these studies will give us a stronger understanding of the mechanisms involved in activation of fXI in pathologic coagulation, and may identify novel targets or pathways that could be targeted with novel therapeutic strategies to treat or prevent thromboembolic disease.

项目摘要 凝血因子（f）XI是凝血蛋白酶fXIa的酶原，在正常的血液凝固中起有限的作用 （止血），因为fXI缺乏与相对轻度的出血倾向相关。尽管如此， 狒狒、兔子和小鼠的研究，得到了人类人口数据的支持，强烈表明fXI使 导致病理性凝血（血栓栓塞）。在经典凝血模型中，fXI被转化为 fXIa在称为接触激活的过程中被激活的fXII（fXIIa）激活，这也需要前激肽释放酶蛋白 (PK)和高分子量激肽原（HK）。接触激活与止血的相关性已被 由于缺乏fXII、PK或HK的患者不会异常出血，因此值得怀疑。基于此，在较新的 止血模型fXI通过不同于接触激活的机制被激活。然而，老鼠 缺乏fXII，类似于缺乏fXI的那些，对血栓形成有抵抗力，这表明接触激活（或过程 类似于它）有助于病理性凝血。尽管现有的流行病学数据在以下方面存在矛盾， 接触激活对人类血栓形成的重要性，我们注意到fXII有助于纤维蛋白形成 以及在离体流动模型中人血液中的血小板聚集。我们假设fXII通过 接触活化或相关过程有助于小鼠中病理性血栓形成和稳定性， 灵长类动物，并且抑制该过程可以产生抗血栓形成作用。在本提案的目标1中， 将通过使用以下方法解决fXI必须与血小板相互作用以促进血栓形成的假设： 转染技术允许蛋白质在体内瞬时表达。我们还将调查 fXla可能通过与其经典功能相关的过程不同的过程促进凝血 激活因子IX目的2中的研究将使用嵌合和非嵌合抗体来研究fXI与fXIIa的相互作用。 突变重组蛋白、常规凝血测定和全血流模型。我们还将 检查fXI-HK相互作用的重要性和PK缺乏对血栓形成的影响， 小鼠以前我们已经证明，fXI缺乏在细菌性脑膜炎模型中赋予小鼠存活优势， 感染在目标3中，我们将比较fXI缺乏对存活率、弥散性血管内 在多微生物脓毒症模型中， 小鼠我们已经证明，用抗体抑制fXI对肿瘤细胞的生长有显著的影响。 狒狒血管移植物血栓形成模型中的富血小板血栓。在目标4中，我们将比较fXI 和fXII抑制，以确定fXII是否在病理性血栓的生长中发挥重要作用 灵长类动物这些研究的结果将使我们更好地了解参与的机制， 在病理性凝血中激活fXI，并可能鉴定可靶向的新靶点或途径。 用新的治疗策略来治疗或预防血栓栓塞性疾病。