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Molecular analysis of heterogeneity in human platelet aggregation response

人血小板聚集反应异质性的分子分析

基本信息

批准号：
17590482
负责人：
SHOJI Masaru
金额：
$ 2.24万
依托单位：
Hirosaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

There is a significant inter-individual divergence in the platelet aggregation response to arginine vasopressin (AVP). In the present study, high-throughput microarray analysis was conducted to explore molecules, which are responsible for the heterogeneity. Responders and non-responders were divided using platelet aggregation analyzer MCM hematracer 313 (Model PAM-12C). Hitachi Ace-Gene micro array analysis showed characteristic gene expression profiling. Namely, responder platelets had increased gene expressions of sodium channel, voltage-gated, type., alpha, mannose-P-dolichol utilization defect 1、eukaryotic translation termination factor 1、cysteine and glycine-rich protein 2、and general transcription factor IIH, polypeptide 2,44kDa. In non-responder platelets, genes including component of oligomeric golgi complex 6、Hermansky-Pudlak syndrome 3、PERM domain containing 1、adenosine monophosphate deaminase 2 (isoform L) nudix-type motif 1、and cell growth regulator with ring finger domain 1 were upregulated. Mass spectrometry analysis demonstrated increased platelet protein levels of protease serine 4 isoform B、and keratin 1b、trypsin family in responders and of TPMsk1、TPM3 protein、and YWHAZ protein in non-responders. There were also increased microRNA levels including hsa let 7d、hsa let 7e、hsa miR 198、hsa miR 99b、and hsa miR 98 in AVP stimulated peripheral CD34(+) stem cells (megakaryocyte progenitor cells). AVP Vla receptor gene polymorphism 242C/T showed an association with its gene expression. From these results, numbers of factors were likely to be responsible for the inter-individual heterogeneity in the platelet aggregation response to AVP.

血小板对精氨酸加压素（AVP）的聚集反应存在明显的个体差异。在本研究中，高通量微阵列分析进行探索分子，这是负责的异质性。使用血小板聚集分析仪MCM hematracer 313（Model PAM-12 C）将应答者和无应答者分开。Hitachi Ace-Gene微阵列分析显示特征性基因表达谱。也就是说，反应血小板增加了钠通道，电压门控，型，α，甘露糖-β-多萜醇利用缺陷1，真核翻译终止因子1，富含半胱氨酸和甘氨酸的蛋白2，和一般转录因子IIH，多肽2，44 kDa。在无应答血小板中，包括寡聚高尔基体复合物6、Hermansky-Pudlak综合征3、含PERM结构域1、腺苷一磷酸脱氨酶2（亚型L）nudix型基序1和具有环指结构域1的细胞生长调节剂的基因上调。质谱分析表明，应答者中蛋白酶丝氨酸4亚型B和角蛋白1 B、胰蛋白酶家族的血小板蛋白水平增加，无应答者中TPMsk 1、TPM 3蛋白和YWHAZ蛋白水平增加。在AVP刺激的外周血CD 34（+）干细胞（巨核细胞祖细胞）中也有增加的microRNA水平，包括hsa let 7 d、hsa let 7 e、hsa miR 198、hsa miR 99 b和hsa miR 98。AVP Vla受体基因多态性242 C/T与其基因表达相关。从这些结果来看，许多因素可能是造成血小板对AVP聚集反应的个体间异质性的原因。