Antithrombotic Activity of Ascidian Glycosaminoglycans

海鞘糖胺聚糖的抗血栓活性

• 批准号: 6622188
• 负责人: DOUGLAS M TOLLEFSEN
• 金额: $ 4.03万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6622188
• 关键词: Tunicata; activation product; anticoagulants; antithrombins; blood coagulation; carbohydrate structure; coagulation factor X; crystallization; disease /disorder model; enzyme inhibitors; gel filtration chromatography; genetically modified animals; hemorrhage; hemostasis; heparin; intermolecular interaction; laboratory mouse; laboratory rat; molecular weight; mucopolysaccharides; nuclear magnetic resonance spectroscopy; platelet activation; platelets; serine proteinases; venous thrombosis

DESCRIPTION (provided by applicant) Heparin from porcine or bovine tissues is used to treat diseases such as venous thrombosis, pulmonary embolism, and coronary artery thrombosis. The anticoagulant effects of heparin result from binding to antithrombin and heparin cofactor II (HCII), which are thereby activated to inhibit thrombin and other coagulation enzymes. Dermatan sulfate is a related polymer that specifically activates HCII. Dermatan sulfates and heparin isolated from the marine invertebrates Styela plicata and Ascidia nigra differ from mammalian glycosaminoglycans in the degree and position of sulfation. These differences have profound effects on their anticoagulant properties in vitro, including their ability to activate antithrombin and HCII. In the present study, ascidian glycosaminoglycans will be compared with their mammalian counterparts to determine the relative contributions of HCII and antithrombin to the antithrombotic activities of heparin and dermatan sulfate. The specific aims are as follows: (1) Prepare low molecular weight derivatives of ascidian glycosaminoglycans, characterize their structures by nuclear magnetic resonance spectroscopy, and determine their anticoagulant activities in vitro. (2) Compare the anticoagulant properties of ascidian dermatan sulfate and heparin with their low molecular weight derivatives in vivo. (3) Investigate the antithrombotic activity of the ascidian glycosaminoglycans in experimental venous and arterial thrombosis models in rats and in normal or HCII-deficient mice. (4) Study the effects of the ascidian glycosaminoglycans and their low molecular weight derivatives on platelet function and determine the hemorrhagic effects of these polymers in vivo. These studies will provide insight into the antithrombotic mechanisms of glycosaminoglycans and may lead to development of anticoagulants with fewer side effects, improved pharmacokinetics, or greater potency than standard heparin preparations. This research will be done primarily in Brazil as an extension of NIH grant 5 R0l HL 55520-05.

描述（由申请人提供） 来自猪或牛组织的肝素用于治疗诸如静脉炎的疾病。 血栓形成、肺栓塞和冠状动脉血栓形成。的 肝素的抗凝作用是由于与抗凝血酶结合， 肝素辅因子II（HCII），其因此被激活以抑制凝血酶， 其他凝固酶。硫酸皮肤素是一种相关的聚合物， 专门激活HCII。皮肤素硫酸盐和肝素分离自 海洋无脊椎动物Styela plicata和Ascidia nigra不同于哺乳动物 硫酸化的程度和位置。这些差异 在体外对它们的抗凝特性有深远的影响，包括 它们激活抗凝血酶和HCII的能力。在本研究中，海鞘 糖胺聚糖将与它们的哺乳动物对应物进行比较， 确定HCII和抗凝血酶对 肝素和硫酸皮肤素的抗血栓形成活性。具体目标 具体如下：（1）海鞘低分子量衍生物的制备 糖胺聚糖，通过核磁共振表征其结构 光谱，并测定其体外抗凝活性。（二） 海鞘硫酸皮肤素与肝素抗凝性能的比较 与它们的低分子量衍生物在体内接触。(3)探讨 海鞘糖胺聚糖的抗血栓活性 大鼠静脉和动脉血栓形成模型以及正常或HCII缺乏的大鼠静脉和动脉血栓形成模型 小鼠(4)海鞘糖胺聚糖及其低聚物的作用研究 分子量衍生物对血小板功能的影响，并确定出血性 这些聚合物在体内的作用。这些研究将提供深入了解 糖胺聚糖的抗血栓形成机制，并可能导致 副作用更少、药代动力学更好或更大的抗凝剂 比标准肝素制剂更有效。 这项研究将主要在巴西进行，作为美国国立卫生研究院赠款的延伸。 R01 HL 55520-05。