Antithrombotic Activity of Ascidian Glycosaminoglycans

海鞘糖胺聚糖的抗血栓活性

• 批准号: 6696337
• 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 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696337
• 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静脉血栓等疾病 血栓形成、肺栓塞和冠状动脉血栓形成。这 肝素的抗凝作用是由于与抗凝血酶结合而产生的 肝素辅因子 II (HCII)，从而被激活以抑制凝血酶和 其他凝固酶。硫酸皮肤素是一种相关聚合物 特异性激活 HCII。硫酸皮肤素和肝素分离自 海洋无脊椎动物 Styela plicata 和 Ascidia nigra 与哺乳动物不同 糖胺聚糖的硫酸化程度和位置。这些差异 对其体外抗凝特性有深远影响，包括 他们激活抗凝血酶和 HCII 的能力。在本研究中，海鞘 糖胺聚糖将与其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活性。具体目标 具体如下： (1)制备海鞘低分子衍生物 糖胺聚糖，通过核磁共振表征其结构 光谱法，并测定其体外抗凝血活性。 (2) 比较海鞘硫酸皮肤素和肝素的抗凝特性 及其在体内的低分子量衍生物。 (3) 调查 海鞘糖胺聚糖的抗血栓活性实验 大鼠以及正常或 HCII 缺陷的静脉和动脉血栓形成模型 老鼠。 (4) 研究海鞘糖胺聚糖的作用及其低 分子量导数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 糖胺聚糖的抗血栓机制，并可能导致 副作用较少、药代动力学改善或效果更好的抗凝剂 效力高于标准肝素制剂。 这项研究将主要在巴西进行，作为 NIH 拨款的延伸 5 R0l HL 55520-05。

项目成果

Isolation and characterization of a heparin with low antithrombin activity from the body of Styela plicata (Chordata-Tunicata). Distinct effects on venous and arterial models of thrombosis.

从褶皱海鞘 (Chordata-Tunicata) 体内分离和表征具有低抗凝血酶活性的肝素。

• DOI: 10.1016/j.thromres.2007.03.025
• 发表时间: 2007
• 期刊: Thrombosis research
• 影响因子: 7.5
• 作者: Santos,JoanaC;Mesquita,JulianaMF;Belmiro,CelsoLR;daSilveira,CarolinaBM;Viskov,Christian;Mourier,PierreA;Pavão,MauroSG
• 通讯作者: Pavão,MauroSG

Collagen colocalizes with a protein containing a decorin-specific peptide in the tissues of the ascidian Styela plicata.

胶原蛋白与含有核心蛋白聚糖特异性肽的蛋白质共定位于海鞘海鞘组织中。

• DOI: 10.1016/j.cbpb.2006.02.013
• 发表时间: 2006
• 期刊: Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.
• 作者: Gandra,Mario;Kozlowski,ElieneO;Andrade,LeonardoR;deBarros,CintiaM;Pascarelli,BernardoMO;Takiya,ChristinaM;Pavao,MauroSG
• 通讯作者: Pavao,MauroSG