腹型HSP儿童血清差异蛋白质组学的研究
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摘要
HSP是临床上儿科常见的血管炎性病变之一，它的发病机制复杂，多年的研究认为其发病机制主要是IgA介导的免疫反应，由于机体被感染、食物、药物等致敏物质致敏发生变态反应，引起广泛小动脉和毛细血管通透性增加，伴有组织的渗出性出血和水肿。导致系统性免疫性血管炎；同时IgA可能激活补体旁路，过多的免疫复合物不能被巨噬细胞清除，刺激部分血管活性物质释放，致使血管壁通透性增加，组织水肿，免疫复合物在血管壁或肾小球膜上沉积，局部组织、血管损伤加剧。HSP的主要病理变化为全身小血管炎，除毛细血管外，也可累及微动脉和微静脉。腹型HSP为HSP常见的一种类型，常以突然发作的阵发性腹部绞痛为特点，通常腹痛症状出现在典型的皮疹之前，给临床诊断带来一定的困难，容易误诊为急腹症，延误治疗或使患儿遭遇不必要的手术治疗。
蛋白质组学技术的发展已经成为现代生物技术快速发展的重要支柱，目前国内外尚无腹型HSP的血清差异蛋白表达的相关报道，本研究的目的是应用蛋白质组学里先进的DIGE技术和TOF/TOF-MS，探讨儿童腹型HSP的差异蛋白质表达，以从蛋白质水平上探讨腹型HSP的发病机制，为疾病诊断和判断预后提供分子标识，以及为预防和治疗药物的研发提供分子靶点。
本研究对象为腹型HSP、急性阑尾炎、体检正常的儿童，留取血清，拟从血清蛋白质组学水平研究腹型HSP患儿的差异表达蛋白，以期能寻找到有助于腹型HSP患儿诊断和治疗的生物学指标。利用Sigma公司的SepproIgY14Spin Columns去除血清中的14种高丰度蛋白后，DIGE系统制备分析胶，Typhoon9400荧光扫描仪和DeCyder全自动差异分析软件分析分析胶并自动匹配后应用DeCyder-BVA软件进行数据分析。将蛋白质含量升高或降低1.5倍，P<0.05，至少在三次重复实验中重复出现的蛋白质点确认为有意义的差异蛋白点，共55个。将制备胶上对应的55个差异表达蛋白点进行TOF/TOF-MS鉴定和MASCOT数据库检索，共鉴定出差异点36个，其中有12个点为重复蛋白质点，紫癜组和阑尾组的显著差异表达蛋白共13个，3个蛋白在紫癜组表达上调，3个蛋白在紫癜组表达下调，4个蛋白在阑尾组表达上调，4个蛋白在阑尾组表达下调。另有2个蛋白各对应2个蛋白点在两组的表达结果不一致。检索得分（SCORE）平均在200分以上(平均85分为及格)，生物信息学分析显示这些蛋白分别具有氨基酸生物合成、细胞应激反应、翻译/生长因子、酶代谢、辅因子和生长因子的生物合成、氨基酸生物合成/转录调控、翻译等功能，其中重要的是：①补体C4B3的过度表达与HSP引起的体途径激活有关，与文献报道相符；②α1-抗胰蛋白酶(A1antchymotrypsin，α1-ACT)、触珠蛋白（Haptoglobin，HP）为急性期反应蛋白，考虑其参与了HSP的变态反应；③纤维蛋白原γ的过度表达考虑与HSP时纤溶系统激活和高凝状态有关；④另外有3个还未命名的蛋白质可能在HSP的发病机制中扮演重要角色。以上这些蛋白有可能成为腹型HSP的分子标志物和药物治疗的靶向蛋白。未知蛋白的进一步研究，可能会有新的发现，具有重要的科学意义和社会意义。
我们继续应用real-time PCR方法验证腹型HSP和急性阑尾炎两组之间的血清差异表达蛋白在RNA水平上的变化。结果显示，部分蛋白质表达和mRNA表达水平有一定的相关性。
本研究通过对腹型HSP的血清蛋白质组学的研究发现的差异表达蛋白质，在国内外均无相关报道，像补体C4B3、纤维蛋白原γ、触珠蛋白、载脂蛋白E等的过度表达，可能构建腹型HSP发病机制新的假说、成为新的诊断标识分子，具有重要的研究意义和广泛的应用前景。蛋白质组学研究是纷繁复杂的工作，因为条件所限，本研究存在一定的不足之处，还需要较大的工作量，在未来的研究中进一步充实和完善试验结果。
Henoch-schonlein purpura (HSP) is a common pediatric disease which iscaused by vascular inflammation changes. It’s pathogenesis is verycomplex.Overreaction to infection, foods or drugs within human body lead toextensive permeability change of little artery and capillary associated withtissue edema and bleeding which is caused by IgA-mediated immunologicalchanges. IgA can activate complement bypass program and excessive immunecomplex result in release of vaso-active substance which lead to increasingvasopermeability and tissue edema. Eventually,exposit of immune complexwithin vascular walls or renal glomerulus membranes aggravate tissue andvascular injuries.
Pathological change of HSP represent with diffuse inflammation of smallvessels including arteriola and venula besides capillaries. HSP with abdominalinvolvement is a common type of pediatric HSP and characterized by acuteand paroxysm colic abdominal pain followed by typical erythra. Because of thelate presentation of the erythra,HSP with abdominal involvement is difficult tobe diagnosed accurately and mistakes are always taken to treat it surgically justas the common acute abdominal disease.
Proteomics is a advanced area of modern biotechnological techniques.Untill now,there were not reports about the serum different protein expresswithin HSP with abdominal involvement. In this study, advanced differentialin-gel electrophoresis and TOF/TOF MS are employed to explore differentprotein express within paediatric HSP with abdominal involvement andinvestigate the mechanism, diagnostic method and prognosis evaluation. Themolecular target is also studied for prevetion and medicine development.
The serum samples,which are taken from children patients with HSP withabdominal involvement and acute appendicitis and normal ones,are studied forthe different protein express within paediatric HSP with abdominalinvolvement and biological index is investigated for treatment and diagnosis ofpediatric HSP with abdominal involvement.
14serum High-abundance proteins are removed by Seppro IgY14SpinColumns(Sigma),analysis gel are produced with differential in-gelelectrophoresis system.The gels are analyzed with Typhoon9400fluorescentscanner and DeCyder automatic difference analysis system followed byanalysis throgh DeCyder-BVA software.55protein points are regarded assignificant points,in which protein volume arise or decrease1.5times,P<0.05,appear more than3times.55significant different express proteinpoints are analyzed with TOF/TOF-MS and MASCOT database.Amongthem,there are13differential expression proteins of HSP group and acuteappendicitis group,including3arising proteins and3decreasing proteins inHSP group,4arising proteins and4decreasing proteins in acute appendicitisgroup.Other2proteins have different expression in HSP group and in acuteappendicitis group,which need to be studied furtherly.The scores are200inaverage. It is documented by bioinformaion analysis that those proteins playroles in amino-acid biosynthesis、amino-acid biosynthesis/structural protein、translation、 energy-metabolism、 biosynthesis of cofactors/Isomerase/growth-factor、 amino-acid biosynthesis/transcription regulationetc.Overexpression of complement C4B3is associated with complementpathway activation the same as report.α1-antitrypsin and haptoglobin are acutephase proteins and may take part in HSP’s allergic reaction.Overexpression offibrinogen γ are related to fibrinolytic system activation and hypercoagulativestate in HSP. In addition there are3unnamed proteins may be associate withthe mechanism of HSP with abdominal involvement.The above proteins may become molecular markers of HSP or targeting proteins for pharmaceuticaltreatment.
The levels of serum differential expression proteins’s RNAexpression are studied with real-time PCR between HSP with abdominalinvolvement group and acute appendicitis group. It is shown that proteinexpression is associated with mRNA expression.
In this study,the serum different protein expression in HSP withabdominal involvement is investigated with proteomics technology andoverexpression of complement C4B3、fibrinogen γ、haptoglobin、apolipoproteinE etc. May construct a new hypothesis about the mechanism of HSP withabdominal involvement,and may be taken as marker for diagnosis of HSP withabdominal involvement.The study has important significance and wideapplication prospect.Proteomics is a complex work,because of the limitedconditions,this study has some deficiency,we need work harder in order tofurther enrich and perfect the test results.
蛋白质组学技术的发展已经成为现代生物技术快速发展的重要支柱，目前国内外尚无腹型HSP的血清差异蛋白表达的相关报道，本研究的目的是应用蛋白质组学里先进的DIGE技术和TOF/TOF-MS，探讨儿童腹型HSP的差异蛋白质表达，以从蛋白质水平上探讨腹型HSP的发病机制，为疾病诊断和判断预后提供分子标识，以及为预防和治疗药物的研发提供分子靶点。
本研究对象为腹型HSP、急性阑尾炎、体检正常的儿童，留取血清，拟从血清蛋白质组学水平研究腹型HSP患儿的差异表达蛋白，以期能寻找到有助于腹型HSP患儿诊断和治疗的生物学指标。利用Sigma公司的SepproIgY14Spin Columns去除血清中的14种高丰度蛋白后，DIGE系统制备分析胶，Typhoon9400荧光扫描仪和DeCyder全自动差异分析软件分析分析胶并自动匹配后应用DeCyder-BVA软件进行数据分析。将蛋白质含量升高或降低1.5倍，P<0.05，至少在三次重复实验中重复出现的蛋白质点确认为有意义的差异蛋白点，共55个。将制备胶上对应的55个差异表达蛋白点进行TOF/TOF-MS鉴定和MASCOT数据库检索，共鉴定出差异点36个，其中有12个点为重复蛋白质点，紫癜组和阑尾组的显著差异表达蛋白共13个，3个蛋白在紫癜组表达上调，3个蛋白在紫癜组表达下调，4个蛋白在阑尾组表达上调，4个蛋白在阑尾组表达下调。另有2个蛋白各对应2个蛋白点在两组的表达结果不一致。检索得分（SCORE）平均在200分以上(平均85分为及格)，生物信息学分析显示这些蛋白分别具有氨基酸生物合成、细胞应激反应、翻译/生长因子、酶代谢、辅因子和生长因子的生物合成、氨基酸生物合成/转录调控、翻译等功能，其中重要的是：①补体C4B3的过度表达与HSP引起的体途径激活有关，与文献报道相符；②α1-抗胰蛋白酶(A1antchymotrypsin，α1-ACT)、触珠蛋白（Haptoglobin，HP）为急性期反应蛋白，考虑其参与了HSP的变态反应；③纤维蛋白原γ的过度表达考虑与HSP时纤溶系统激活和高凝状态有关；④另外有3个还未命名的蛋白质可能在HSP的发病机制中扮演重要角色。以上这些蛋白有可能成为腹型HSP的分子标志物和药物治疗的靶向蛋白。未知蛋白的进一步研究，可能会有新的发现，具有重要的科学意义和社会意义。
我们继续应用real-time PCR方法验证腹型HSP和急性阑尾炎两组之间的血清差异表达蛋白在RNA水平上的变化。结果显示，部分蛋白质表达和mRNA表达水平有一定的相关性。
本研究通过对腹型HSP的血清蛋白质组学的研究发现的差异表达蛋白质，在国内外均无相关报道，像补体C4B3、纤维蛋白原γ、触珠蛋白、载脂蛋白E等的过度表达，可能构建腹型HSP发病机制新的假说、成为新的诊断标识分子，具有重要的研究意义和广泛的应用前景。蛋白质组学研究是纷繁复杂的工作，因为条件所限，本研究存在一定的不足之处，还需要较大的工作量，在未来的研究中进一步充实和完善试验结果。
Henoch-schonlein purpura (HSP) is a common pediatric disease which iscaused by vascular inflammation changes. It’s pathogenesis is verycomplex.Overreaction to infection, foods or drugs within human body lead toextensive permeability change of little artery and capillary associated withtissue edema and bleeding which is caused by IgA-mediated immunologicalchanges. IgA can activate complement bypass program and excessive immunecomplex result in release of vaso-active substance which lead to increasingvasopermeability and tissue edema. Eventually,exposit of immune complexwithin vascular walls or renal glomerulus membranes aggravate tissue andvascular injuries.
Pathological change of HSP represent with diffuse inflammation of smallvessels including arteriola and venula besides capillaries. HSP with abdominalinvolvement is a common type of pediatric HSP and characterized by acuteand paroxysm colic abdominal pain followed by typical erythra. Because of thelate presentation of the erythra,HSP with abdominal involvement is difficult tobe diagnosed accurately and mistakes are always taken to treat it surgically justas the common acute abdominal disease.
Proteomics is a advanced area of modern biotechnological techniques.Untill now,there were not reports about the serum different protein expresswithin HSP with abdominal involvement. In this study, advanced differentialin-gel electrophoresis and TOF/TOF MS are employed to explore differentprotein express within paediatric HSP with abdominal involvement andinvestigate the mechanism, diagnostic method and prognosis evaluation. Themolecular target is also studied for prevetion and medicine development.
The serum samples,which are taken from children patients with HSP withabdominal involvement and acute appendicitis and normal ones,are studied forthe different protein express within paediatric HSP with abdominalinvolvement and biological index is investigated for treatment and diagnosis ofpediatric HSP with abdominal involvement.
14serum High-abundance proteins are removed by Seppro IgY14SpinColumns(Sigma),analysis gel are produced with differential in-gelelectrophoresis system.The gels are analyzed with Typhoon9400fluorescentscanner and DeCyder automatic difference analysis system followed byanalysis throgh DeCyder-BVA software.55protein points are regarded assignificant points,in which protein volume arise or decrease1.5times,P<0.05,appear more than3times.55significant different express proteinpoints are analyzed with TOF/TOF-MS and MASCOT database.Amongthem,there are13differential expression proteins of HSP group and acuteappendicitis group,including3arising proteins and3decreasing proteins inHSP group,4arising proteins and4decreasing proteins in acute appendicitisgroup.Other2proteins have different expression in HSP group and in acuteappendicitis group,which need to be studied furtherly.The scores are200inaverage. It is documented by bioinformaion analysis that those proteins playroles in amino-acid biosynthesis、amino-acid biosynthesis/structural protein、translation、 energy-metabolism、 biosynthesis of cofactors/Isomerase/growth-factor、 amino-acid biosynthesis/transcription regulationetc.Overexpression of complement C4B3is associated with complementpathway activation the same as report.α1-antitrypsin and haptoglobin are acutephase proteins and may take part in HSP’s allergic reaction.Overexpression offibrinogen γ are related to fibrinolytic system activation and hypercoagulativestate in HSP. In addition there are3unnamed proteins may be associate withthe mechanism of HSP with abdominal involvement.The above proteins may become molecular markers of HSP or targeting proteins for pharmaceuticaltreatment.
The levels of serum differential expression proteins’s RNAexpression are studied with real-time PCR between HSP with abdominalinvolvement group and acute appendicitis group. It is shown that proteinexpression is associated with mRNA expression.
In this study,the serum different protein expression in HSP withabdominal involvement is investigated with proteomics technology andoverexpression of complement C4B3、fibrinogen γ、haptoglobin、apolipoproteinE etc. May construct a new hypothesis about the mechanism of HSP withabdominal involvement,and may be taken as marker for diagnosis of HSP withabdominal involvement.The study has important significance and wideapplication prospect.Proteomics is a complex work,because of the limitedconditions,this study has some deficiency,we need work harder in order tofurther enrich and perfect the test results.
引文
[1]胡亚美，江载芳.诸福棠实用儿科学[M]．北京：人民卫生出版社，2002：688-690．
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