Establishment of the platelet disorders characterized by impaired signal transduction

以信号转导受损为特征的血小板疾病的建立

• 批准号: 14570968
• 负责人: FUSE Ichiro
• 金额: $ 1.92万
• 依托单位: NIIGATA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570968/
• 关键词: thromboxane receptor; ADP receptor; P2X1 receptor; F2Y12 receptor; Platelet signal transduction disease; 血小板刺激伝達異常性

Ca^<2+> ionophores such as A23187 and ionomycin, which transport divalent cations across membranes, were reported to induce platelet activation. Several evidences suggested that secretion and phospholipase C activation induced by Ca^<2+> ionophore are totally dependent upon intact thromboxane. This suggests that platelets with impaired thromboxane formation or impaired response to thromboxane show defective Ca^<2+> ionophore-induced platelet aggregation. In fact, we previously reported that Ca^<2+> ionophore A23187-induced platelet aggregation was markedly reduced in patients with congenital platelet cyclo-oxygenase or with defective TXA_2-induced platelet aggregation. As to the latter disorder, we clarified that Arg^<60> to Leu mutation in the first cytoplasmic loop of the TXA_2 receptor(TXR) causes impaired coupUng between TXR and phoshoplipase C activation.On the other hand, several cases with bleeding tendencies whose platelets respond defectively to Ca^<2+> ionophore without those causes have been reported However, since these cases are rare, the defective site has not been fully elucidated.We analyzed the effect of PGE_1-induced increase in platelet cAMP levels and its inhibition by ADP and epinephrine hi three patients characterized by impaired ADP-induced platelet aggregation. We found that ADP as well as epinephrine lowered the PGE_1-induced cAMP increase in the patient's platelets. This suggests that the patient does not have a defect of the platelet P2Y_<12> receptor for ADP, since, in the patients with this defect, it was reported that epinephrine normally lowered the PGE_1-stimulated platelet cAMP increase, but ADP was without effect. These findings suggest that the defective site in the patients' platelets lies in the process distal to or independent of protein kinase C activation, Ca^<2+> mobilization and MLC phosphorylation.

据报道，钙离子载体，如A23187和离子霉素，可以跨膜运输二价阳离子，诱导血小板激活。一些证据表明，钙离子载体诱导的分泌和磷脂酶C激活完全依赖于完整的血栓素A。这表明血栓素形成受损或对血栓素反应受损的血小板表现出缺陷的钙离子载体诱导的血小板聚集。事实上，我们以前报道过，在患有先天性血小板环氧合酶或TXA2诱导的血小板聚集缺陷的患者中，钙离子载体A23187诱导的血小板聚集显著减少。对于后一种疾病，我们阐明了血栓素A_2受体(TXR)第一胞浆环上的亮氨酸突变导致TXR和磷脂酶C激活之间的偶联受损。另一方面，有出血倾向的几例患者的血小板对Ca~(2+)&GT；离子载体的反应障碍已有报道，但由于这种情况很少见，缺陷部位尚未完全阐明。我们分析了PGE_1诱导的血小板cAMP水平升高以及ADP和肾上腺素抑制三例以ADP诱导的血小板聚集为特征的患者的作用。我们发现ADP和肾上腺素降低了PGE_1诱导的患者血小板内cAMP的增加。这表明患者并不存在血小板P2Y；12&GT；ADP受体缺陷，因为据报道，在有这种缺陷的患者中，肾上腺素通常会降低PGE_1刺激的血小板cAMP升高，而ADP则没有作用。这些发现表明，患者血小板中的缺陷部位位于蛋白激酶C激活、Ca~(2+)&gt；动员和MLC磷酸化的远端或独立的过程中。

项目成果

Fuse I: "Congenital thrombhoxane receptor abnormality"SOGORINSYO. 52. 1643-1646 (2003)

保险丝一：“先天性血栓素受体异常”SOGORINSYO。

Ichiro Fuse, et al.: "DDAVP normalized the bleeding time in patients with platelet disorder characterized by defective calcium ionophore-induced platelet aggregation"British Journal of Haematology. 122. 870-871 (2003)

Ichiro Fuse 等人：“DDAVP 使血小板疾病患者的出血时间正常化，其特征是钙离子载体缺陷诱导的血小板聚集”《英国血液学杂志》。

Ichiro Fuse: "DDAVP normalized the bleeding time in patients with congenital thromboxane A_2 receptor abnormality"Transfusion. 43. 563-567 (2003)

Ichiro Fuse：“DDAVP 使先天性血栓素 A_2 受体异常患者的出血时间正常化”输血。

布施一郎: "血小板生物学"メディカルレビュー社(2004年発行予定). (2004)

布施一郎：《血小板生物学》医学评论出版（预定2004年出版）（2004年）。

Fuse I et al.: "DDAVP normalized the bleeding time in patients with platelet disorder characterized by defective calcium ionophore-induced platelet aggregation."British J Haematol. 122. 870-871 (2003)

Fuse I 等人：“DDAVP 使患有血小板疾病的患者的出血时间正常化，其特征是钙离子载体缺陷诱导的血小板聚集。”英国 J Haematol。