PLATELET/HEPARIN INTERACTIONS IN CARDIOVASCULAR SURGERY

心血管手术中血小板/肝素的相互作用

• 批准号: 2028361
• 负责人: MICHAEL SOBEL
• 金额: $ 21.46万
• 依托单位: VETERANS HEALTH RESEARCH INSTITUTE OF CENTRAL NEW YORK, INC.
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2028361
• 关键词: affinity chromatography; affinity labeling; anticoagulants; binding proteins; calorimetry; carbohydrate structure; cardiovascular surgery; chemical structure function; heparin; human tissue; oligosaccharides; platelet activation; platelet aggregation; platelets; protein sequence; radiotracer; receptor binding; thrombosis; von Willebrand factor

The aim of this research is to elucidate the fundamental structure- function relations of heparin~s interactions with von Willebrand factor, and blood platelets. Heparin is an essential drug for cardiovascular surgery. The main clinical problem is that the salutary anticoagulant effects of pharmaceutical heparin have been married to hemorrhagic, immunogenic, and platelet stimulating side effects. The clinical use of heparin has been a compromise because it has not been possible to capitalize on the many distinct biological activities now being discovered. The main scientific problem has been a lack of understanding of the fundamental structure-function relations of heparin~s interactions with proteins and cells. In previous work, we have established that heparin binds to a specific domain of von Willebrand factor (V.F.), interfering with its platelet adhesive effects via the platelet receptor Gplb. We have refined subspecies of heparin with 7-8 fold increased potency to inhibit V.F.-dependent platelet function, but with only 10% of normal anticoagulant potency. We have defined important structural features of heparin responsible for direct platelet binding, and begun identification of heparin binding sites on the platelet surface. In our future work, we plan to 1) Define the optimal glycosaminoglycan structure responsible for heparin inhibition of V.F.-mediated thrombosis, using structure-specific modifications and synthetic oligosaccharides, in vitro and in vivo biological assessments, and structural analysis; 2) Elucidate the mechanism(s) by which heparin binds V.F. and exerts its inhibitory effects, through biophysical analyses an photoaffinity labeling; and 3) Define the mechanisms of heparin~s direct effects on platelet function, through structural analysis of heparins and identification of platelet surface proteins that bind heparin. Our long germ goal is the development of novel heparin-based antithrombotic drugs with unique, focussed biological activities applicable to cardiovascular surgery: heparins that inhibit platelet thrombosis at sites of vascular injury and on bioprosthetic surfaces, and conversely, heparins with low platelet reactivity. In the future, the results of this work should provide research tools and insights useful for explorations of heparin's interactions with other adhesive proteins, vascular growth factors, and smooth muscle cells.

这项研究的目的是阐明基本结构-- 肝素~S与von Willebrand相互作用的函数关系 因子和血小板。 肝素是心血管手术的基本药物。主 临床上的问题是，有益的抗凝作用 药用肝素已经嫁给了出血性， 免疫原性和刺激血小板的副作用。临床应用 肝素是一种妥协，因为它不可能 利用现在许多不同的生物活动 被发现了。主要的科学问题是缺乏 对基本结构-功能关系的理解 肝素~S与蛋白质和细胞的相互作用。 在以前的工作中，我们已经确定肝素与一种 Von Willebrand因子(V.F.)的特异性结构域，干扰其 通过血小板受体Gplb发挥血小板黏附作用。我们有 精制肝素亚种，效力提高7-8倍 抑制V.F.依赖的血小板功能，但只有10% 正常的抗凝血效力。我们已经定义了重要的 负责直接与血小板结合的肝素的结构特征， 并开始鉴定血小板上的肝素结合部位 浮出水面。 在我们未来的工作中，我们计划1)定义最优的 糖胺多聚糖结构与肝素抑制肝素的关系 利用结构特异性修饰的V.F.介导的血栓形成 和人工合成低聚糖，体外和体内生物 评估和结构分析；2)阐明机制(S) 肝素通过与V.F.结合并发挥其抑制作用， 通过生物物理分析进行光亲和标记；以及3) 明确肝素~S直接作用于血小板的机制 功能，通过对肝素的结构分析和鉴定 结合肝素的血小板表面蛋白。 我们的长期目标是开发新型肝素类药物 具有独特、集中生物活性的抗血栓药物 适用于心血管外科：抑制血小板的肝素 血管损伤部位和生物假体表面的血栓形成， 反之，低血小板反应性的肝素。 在未来，这项工作的结果应该会提供研究工具 以及有助于探索肝素与 其他黏附蛋白、血管生长因子和平滑 肌肉细胞。