Antithrombin targeting to HSPG & heparin coated surfaces

针对 HSPG 的抗凝血酶

• 批准号: 7020710
• 负责人: SUSAN C BOCK
• 金额: $ 18.25万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7020710
• 关键词: antithrombin III; antithrombogenic surface; arteriovenous shunt surgery; artery stenosis; bioengineering /biomedical engineering; biotechnology; coagulation factor X; elastases; heparin; intravenous administration; laboratory rabbit; mathematical model; model design /development; protein isoforms; protein transport; proteoglycan; recombinant proteins; shear stress; surface coating; thrombin

DESCRIPTION (provided by applicant): Activation of thrombin and factor Xa (fXa) occurs on vascular and biomaterial surfaces and initiates coagulation, platelet, signaling and cell proliferation reactions, which may then promote pathological thrombosis, occlusion and restenosis in the native circulatory system and on surfaces of implanted vascular grafts, stents, hemodialysis access grafts and ventricular assist devices. Early intervention via the neutralization of thrombin/fXa molecules as they are generated at blood-surface interfaces would be a widely applicable strategy for reducing thrombin/fXa mediated pathologies. Implementation of this approach will require blood-borne inhibitors to target vascular and biomaterial surfaces and to remain stable under focal and systemic inflammatory conditions. Recombinant human antithrombin Ills (ATllls) developed in our lab inhibit thrombin and fXa with comparable efficiency to endogenous ATIII, but bind heparin with 50x greater affinity and are 10x more resistant to neutrophil elastase cleavage. These "super-beta-ATIN" molecules also target heparin-coated surfaces of an in vitro flow model at least 9x more efficiently than does plasma ATIII. Therefore, early intervention via super-beta-ATIII loading of thrombin/fXa inhibitory activity onto native vascular and heparin-coated biomaterial surfaces may prove generally useful for blocking surface-catalyzed thrombotic, occlusion and restenosis events. As these pathologies develop under widely varying rheological conditions, flow-related factors modulating ATIII surface loading in different vessels and implant applications must be elucidated. Goals of this R21 are to obtain rheological and dosing data to support clinical translation efforts. Aim 1 will investigate mass transport effects on super-beta-ATIII surface delivery under low-vs-high and steady-vs-pulsatile flow, using simulations, an in vitro flow model, and lumenal surface analysis of rabbit blood vessels. Aim 2 will evaluate the ability of super-beta-ATIII to prevent thrombosis in rabbit carotid shunt and stenosis models.

描述（由申请人提供）：凝血酶和因子 Xa (fXa) 的激活发生在血管和生物材料表面，并引发凝血、血小板、信号传导和细胞增殖反应，然后可能促进自然循环系统中的病理性血栓形成、闭塞和再狭窄，植入的血管移植物、支架、血液透析通路移植物和心室辅助装置的表面。通过中和在血液表面界面生成的凝血酶/fXa 分子进行早期干预将是减少凝血酶/fXa 介导的病理的广泛适用的策略。这种方法的实施将需要血源性抑制剂靶向血管和生物材料表面，并在局部和全身炎症条件下保持稳定。我们实验室开发的重组人抗凝血酶 Ills (ATllls) 抑制凝血酶和 fXa 的效率与内源性 ATIII 相当，但与肝素的结合亲和力高出 50 倍，对中性粒细胞弹性蛋白酶裂解的抵抗力高出 10 倍。这些“超级 β-ATIN”分子还靶向体外流动模型的肝素涂层表面，效率至少比血浆 ATIII 高 9 倍。因此，通过在天然血管和肝素涂层生物材料表面加载凝血酶/fXa抑制活性的超β-ATIII进行早期干预可能对阻止表面催化的血栓形成、闭塞和再狭窄事件普遍有用。由于这些病变是在广泛变化的流变条件下发展的，因此必须阐明调节不同血管和植入物应用中 ATIII 表面负荷的流动相关因素。该 R21 的目标是获取流变学和剂量数据以支持临床转化工作。目标 1 将使用模拟、体外流动模型和兔血管的腔表面分析，研究低流与高流以及稳定流与脉动流下的质量传输对 super-β-ATIII 表面递送的影响。目标 2 将评估 super-β-ATIII 在兔颈动脉分流和狭窄模型中预防血栓形成的能力。