Antithrombin targeting to HSPG & heparin coated surfaces
针对 HSPG 的抗凝血酶
基本信息
- 批准号:6913869
- 负责人:
- 金额:$ 21.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-04-01 至 2007-03-31
- 项目状态:已结题
- 来源:
- 关键词:antithrombin IIIantithrombogenic surfacearteriovenous shunt surgeryartery stenosisbioengineering /biomedical engineeringbiotechnologycoagulation factor Xelastasesheparinintravenous administrationlaboratory rabbitmathematical modelmodel design /developmentprotein isoformsprotein transportproteoglycanrecombinant proteinsshear stresssurface coatingthrombin
项目摘要
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Xa因子(fXa)的活化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,然后可能促进自体循环系统和植入血管移植物、支架、血液透析通路移植物和心室辅助器械表面的病理性血栓形成、闭塞和再狭窄。通过中和凝血酶/fXa分子的早期干预,因为它们是在血液表面界面处产生的,将是减少凝血酶/fXa介导的病理学的广泛适用的策略。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,并在局灶性和全身性炎症条件下保持稳定。我们实验室开发的重组人抗凝血酶III(ATIII)以与内源性ATIII相当的效率抑制凝血酶和fXa,但以50倍更高的亲和力结合肝素,并且对中性粒细胞弹性蛋白酶切割的抗性高10倍。这些“超级β-ATIN”分子也靶向体外流动模型的肝素包被表面,其效率比血浆ATIII高至少9倍。因此,通过将凝血酶/fXa抑制活性的超β-ATIII负载到天然血管和肝素涂覆的生物材料表面上的早期干预通常可证明可用于阻断表面催化的血栓形成、闭塞和再狭窄事件。由于这些病理发展在广泛变化的流变条件下,必须阐明在不同血管和植入物应用中调节ATIII表面负荷的流动相关因素。本R21的目标是获得流变学和剂量数据,以支持临床翻译工作。目的1将使用模拟、体外流动模型和兔血管的内腔表面分析,研究在低流与高流和稳态与脉动流下对超β-ATIII表面递送的传质效应。目的2评价super-beta-ATIII在兔颈动脉分流和狭窄模型中预防血栓形成的能力。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(2)
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{{ truncateString('SUSAN C BOCK', 18)}}的其他基金
Development of Cross Protective H5 Hemagglutinin Antigens
交叉保护性 H5 血凝素抗原的开发
- 批准号:
8072917 - 财政年份:2010
- 资助金额:
$ 21.63万 - 项目类别:
Development of Cross Protective H5 Hemagglutinin Antigens
交叉保护性 H5 血凝素抗原的开发
- 批准号:
7880704 - 财政年份:2009
- 资助金额:
$ 21.63万 - 项目类别:
Development of Cross Protective H5 Hemagglutinin Antigens
交叉保护性 H5 血凝素抗原的开发
- 批准号:
7741349 - 财政年份:2009
- 资助金额:
$ 21.63万 - 项目类别:
Conformational change propagation in ATIII-heparin
ATIII-肝素中的构象变化传播
- 批准号:
7331505 - 财政年份:2005
- 资助金额:
$ 21.63万 - 项目类别:
Conformational change propagation in ATIII-heparin
ATIII-肝素中的构象变化传播
- 批准号:
6869382 - 财政年份:2005
- 资助金额:
$ 21.63万 - 项目类别:
Antithrombin targeting to HSPG & heparin coated surfaces
针对 HSPG 的抗凝血酶
- 批准号:
7020710 - 财政年份:2005
- 资助金额:
$ 21.63万 - 项目类别:
Conformational change propagation in ATIII-heparin
ATIII-肝素中的构象变化传播
- 批准号:
6999371 - 财政年份:2005
- 资助金额:
$ 21.63万 - 项目类别:
Conformational change propagation in ATIII-heparin
ATIII-肝素中的构象变化传播
- 批准号:
7155798 - 财政年份:2005
- 资助金额:
$ 21.63万 - 项目类别:
Conformational change propagation in ATIII-heparin
ATIII-肝素中的构象变化传播
- 批准号:
7166099 - 财政年份:2005
- 资助金额:
$ 21.63万 - 项目类别:
SERPIN STRUCTURE AND THE DEVELOPMENT OF NEUTROPHIL RESISTANT SERPINS
Serpin 结构和中性粒细胞抗性 Serpin 的开发
- 批准号:
6485295 - 财政年份:2001
- 资助金额:
$ 21.63万 - 项目类别: