Molecular basis for the fibrinogen structure and functions-Analysis of hereditary dysfibrinogens and their application to the study

纤维蛋白原结构和功能的分子基础-遗传性异常纤维蛋白原的分析及其在研究中的应用

• 批准号: 09044329
• 负责人: MATSUDA Michio
• 金额: $ 1.66万
• 依托单位: Jichi Medical School, School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 无数据
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09044329/
• 关键词: dysfibrinogen; ultrastructure of fibrin; extra glycosylation; cross-linking; thrombosis

1. Studies on the structure-function relationship of hereditary dysfibrinogens : More than 10 samples have been referred to us from the institutions in Japan and from abroad, and the analyzes so far completed have been reported (See the publication list). Among them, we would like to introduce two unique molecules, one from abroad and the other from Niigata. (1) Fibrinogen Marburg : This dysfibrinogen was found in a 20 year-old German lady who manifested severe post-operative bleeding, recurrent thrombo-embolic diseases and would healing disturbance, all apparently related to functional abnormalities of fibrinogen. This molecule has a pair of 150 residues-truncated Aalpha-chains due to premature appearance of a stop codon TAA for AAA coding Aalpha Lys-461. Because of this truncation of the C-terminal (461-610) residues of the Aalpha-chain, Aalpha Cys-442 has lost its disulfide-bridge partner, and is partly disulfide-bridged with serum albumin. On clotting with thrombin, factor XIII and … More Ca^<2+>, part of the Aalpha-linked albumin was cross-linked to the gamma-chain of another fibrin molecules. The cross-linked fibrin was found to be extremely resistant against plasmic digestion, accounting for at least partly the thrombo-embolic complications in the patient. (2) Fibrinogen Niigata : Because of an Asn to Ser mutation at Bbeta-160, a new Asn-X-Ser type sequence is created at Bbeta 158-159-160, and indeed, a biantennary olibosaccharide was found to be N-linked to Bbeta Asn-158. As this mutant segment is spatially apart from the primary polymerization site in the D domain, we have been searching for the mechanism underlying functional abnormalities.2. Analyzes of the ultrastructure of the abnormal fibrin clots : In collaboration with two experts in U.S.A., Michael W.Mosesson and John W.Weisel, we have obtained several important pieces of information on representative molecules selected for our international collaboration studis. The Marburg fibrin clots were found to consist of very thin and highly branched fibers, which give rise to compactly interwoven textures. Liquid permeability studies showed that the Marburg fibrin would allow liquids to flow far less smoothly in their textures than in th normal contrl. The thrombo-embolic diseases and would healing disturbances seem to be partly accounted for by this abnormality. The Niigata fibrin clots were composed of highly branched fibrin fibers and the Kurashiki fibrin clots appeared to be irregular as compared with the normal clots. After removal of the oligosaccharides, the Niigata fibrin fibers were found to be extraordinarily thick and far less branched than the control fibers. The relevance of the structural alteration to these abnormal features are currently under investigation. Less

1。关于遗传不纤维纤维素的结构 - 功能关系的研究：已经从日本和国外向我们转介了10个以上样本，并且迄今已报告了迄今已完成的分析（请参阅出版物列表）。其中，我们想介绍两个独特的分子，一个来自海外的分子，另一个来自Niigata。 （1）纤维蛋白原Marburg：这种失调蛋白原是在一位20岁的德国女士中发现的，该女士表现出严重的术后出血，复发性的血栓栓塞性疾病，并会治愈灾难，这显然与纤维蛋白原功能异常有关。该分子具有一对150个保留截断的Aalpha链，这是由于AAA编码Aalpha Lys-461的终止密码子TAA的过早外观。由于Aalpha链的C端（461-610）保留了这种截断，Aalpha Cys-442失去了其二硫键合作伙伴，并且是Serum专辑的部分二硫键。在带有凝血酶，因子XIII和…更多的Ca^<2+>的衣服上，将Aalpha连锁白蛋白的一部分交联至另一个纤维蛋白分子的伽马链。发现交联的纤维蛋白具有极大的抵抗力对等离子消化，至少部分地占患者的势头 - 栓塞并发症。 （2）纤维蛋白原niigata：由于BBETA-160处的ASN至SER突变，因此在BBETA 158-159-160上创建了一种新的ASN-X-SER型序列，实际上，发现双胞质橄榄石糖是N-link n-link to bbeta asn-158。由于该突变段在空间上与D结构域中的主要聚合位点区分开来，因此我们一直在寻找功能异常的机制。2。异常纤维蛋白血块的超微结构的分析：与美国的两位专家Michael W. Mosesson和John W. Weisel合作，我们已经获得了有关为我们的国际合作研究选择的代表性分子的一些重要信息。发现Marburg纤维蛋白布由非常薄且高度分支的纤维组成，可产生紧凑的交织纹理。液体渗透性研究表明，与正常对照相比，马堡纤维蛋白在质地上的流动水平要低得多。 Thrombo颗粒性疾病和治愈性疾病似乎部分被这种异常解释。 Niigata纤维蛋白簇由高度支蛋白的纤维蛋白纤维组成，与正常簇相比，kurashiki纤维蛋白簇似乎是不规则的。去除寡糖后，发现Niigata纤维蛋白纤维比对照纤维的厚度非常厚，分支要小得多。目前正在研究结构改变与这些异常特征的相关性。较少的

项目成果

坂田 宏: "急性リンパ性白血病の経過中に発見された先天性フィブリノーゲン異常症(fibrinogen Asahikasa II)の1例" 日本小児血液学会雑誌. 11(6). 441-444 (1997)

Hiroshi Sakata：“急性淋巴细胞白血病病程中发现的先天性纤维蛋白原异常（纤维蛋白原 Asahikasa II）”，日本儿科血液学会杂志 11（6）（1997 年）。

Shu-ichi Yamaguchi, Teruko sugo, Yoichiro Hashimoto, Kazumi Kimura, Kenji Okajima and Michio Matsuda: "Fibrinogen Kumamoto with an Aalpha Arg-19 to Gly substitution has reduced affinity for thrombin : Possible relevance to thrombosis." Jpn.J.Thromb.Hemost

Shu-ichi Yamaguchi、Teruko sugo、Yoichiro Hashimoto、Kazumi Kimura、Kenji Okajima 和 Michio Matsuda：“将 Aalpha Arg-19 替换为甘氨酸的熊本纤维蛋白原降低了对凝血酶的亲和力：可能与血栓形成有关。”

ASAKURA,Shinji: "Fibroblasts spread on immobilized fibrin monomer by mobilizing a β1-classintegrin,together with a vitronection receptor αvβ3 on their surface." J.Biol.Chem.272(13). 8824-8829 (1997)

ASAKURA, Shinji：“成纤维细胞通过动员 β1 类整合素以及其表面的玻连接受体 αvβ3 在固定的纤维蛋白单体上扩散。J.Biol.Chem.272(13)。”

Pfitzner,A.Susanne: "Fibrin detected in plasma of patients with disseminated intravascular coagulation by fibrin-specific antibodies consists primarily of high molecular weight factor XIIIa-crosslinked and plasmin-modified complexes partially containing f

Pfitzner，A.Susanne：“通过纤维蛋白特异性抗体在弥散性血管内凝血患者的血浆中检测到的纤维蛋白主要由高分子量因子 XIIIa 交联和纤溶酶修饰的复合物组成，部分含有 f

Michio Matsuda: "The derivatives of human fibrinogen with special reference to soluble fibrin and the D-dimer. Their generation and status in the circulating blood. 2. The D-dimer." Jpn.J.Thromb.Hemost. 8 (3). 204-211 (1997)

Michio Matsuda：“人类纤维蛋白原的衍生物，特别是可溶性纤维蛋白和 D-二聚体。它们在循环血液中的生成和状态。2. D-二聚体。”