变应性鼻炎的血清蛋白质组学研究
摘要
第一章变应性鼻炎的血清蛋白组学研究及生物信息学分析
目的变应性鼻炎是一种十分常见的疾病,它还是哮喘的高危因素。变应原特异性免疫治疗是唯一可以改变变应性鼻炎疾病进程的治疗方法。然而,变应性鼻炎的发病机制及其特异性免疫治疗的确切机制尚未完全阐明。本研究的目的是为了筛选与常年性变应性鼻炎发病及特异性免疫治疗密切相关的调控因子及其调节网络,为进一步深入研究变应性鼻炎及其免疫治疗的作用机制奠定基础。
方法研究选取了45名确诊为常年性变应性鼻炎患者,22名经特异性免疫治疗有效患者,20名经特异性免疫治疗无效患者及20名健康志愿者作为研究对象。我们对这四组研究对象进行了同位素标记的相对和绝对定量的蛋白组学研究,接着利用二维凝胶电泳及质谱分析确定我们所需的差异蛋白。然后利用利用EXPANDER v5.2软件对这些差异蛋白进行聚类分析。最后将聚类后的差异蛋白汇入Metacore软件,进一步确认可能起重要作用的调节网络及与特异性免疫治疗密切相关的蛋白作用。
结果本研究共确认了210个差异蛋白,其中188个与变应性鼻炎的发生密切相关,91个与特异性免疫治疗的作用相关。通过Metacore通路软件构建了p值最小的10组调节通路,其中以凝血通路的可信度最高。其中参与凝血通路的重要蛋白质如凝血因子XⅡ、凝血因子Ⅲ、凝血酶原、α-2巨球蛋白及纤溶酶原等在四组研究对象中表达都有所改变。在变应性鼻炎组中表达增高,经特异性免疫治疗后,在特异性免疫治疗有效组中其表达下降,而在特异性免疫治疗无效组中其表达升高或变化不明显。在Metacore软件构建的转录因子网络中,STAT3及STAT1转录因子网络与凝血通路的相关系数最高。
结论凝血因子XⅡ、凝血因子Ⅲ、凝血酶原、α-2巨球蛋白及纤溶酶原构成的凝血通路很可能是变应性鼻炎炎症反应的重要调节网络。特异性免疫治疗可能通过抑制凝血通路的活化以减轻变应性炎症反应从而改善变应性鼻炎的症状。而且凝血通路可能通过STAT3和／或STAT1转录因子网络参与AR及特应性免疫治疗的调控。
第二章凝血酶Thrombin在AR血清中的鉴定
目的变应性鼻炎是鼻部常见的慢性炎症性疾病,其发病机制一直以来是基础和临床研究的重点,但至今仍不十分清楚。第一章的研究我们已证实凝血通路的激活和抑制可能对变应性鼻炎的炎症反应和特异性免疫治疗的疗效起着重要作用,本章中我们选择凝血通路中起中心作用的调节因子Thrombin蛋白作为研究对象,检测变应性鼻炎及免疫治疗病人中Thrombin蛋白的表达差异。探讨Thrombin蛋白在变应性鼻炎及特异性免疫治疗中的意义；并检验凝血通路与变应性鼻炎及特异性免疫治疗的相关性。
方法利用酶联免疫吸附法检测变应性鼻炎(20例),特异性免疫治疗有效组患者(20例)及特异性免疫治疗无效组患者(20例)血清中Thrombin蛋白的含量,并与健康志愿者(20例)的结果进行统计学比较。
结果三个病例组(变应性鼻炎、特异性免疫治疗有效组、特异性免疫治疗无效组)与健康对照组总体比较,进一步对血清Thrombin水平进行组间两两比较。结果显示：1、变应性鼻炎组血清中thrombin的含量增高与对照组相比较,两组之间差异有显著统计学意义(P<0.001)。2、在特异性免疫治疗有效组中血清中thrombin的含量显著下降与AR组相比其差异亦具有显著统计学意义(P<0.001)；3、在特异性免疫治疗无效组中血清中thrombin的含量升高或变化不明显与SIT无效组相比较其差异亦具显著性(P<0.001)。
结论Thrombin在变应性鼻炎的发生发展中可能发挥了一定的作用；进一步从点的层面上初步验证了凝血通路与变应性鼻炎密切相关的推论；定期检测患者体内的thrombin含量变化或许能预测特异性免疫治疗的疗效及确定SIT的终止时间。然而Thrombin蛋白在变应性鼻炎中及特异性免疫治疗中的作用机制仍有待于进一步深入研究。
Charpter1The study of serum proteomics and bioinformatics analysis on perennial allergic rhinitis
Objective Allergic rhinitis (AR) is a very common disease and a great risk factor for allergic asthma. Allergen specific immunotherapy is a promising method for changingthe course of allergic rhinitis progression. However, the exact mechanisms of the pathogenesis of allergic rhinitis and the specific immunotherapy have not been fully elucidated. The purposes of this study are to identify the regulatory networks active in perennial allergic rhinitis patients and those receiving specific immunotherapy and then to explore the functions of these regulatory networks. Finally, provide the foundation for the further mechanisms of allergic rhinitis and the specific immunotherapy.
Methods45perennial allergic rhinitis patients,22SIT-effective and20SIT-ineffective allergic rhinitis patients and20healthy controls were recruited for this study. Isobaric tags for relative and absolute quantitation followed by two-dimensional gel electrophoresis and mass spectrometry were used to identify proteins that were differentially expressed among the four groups. The proteins that were significantly differentially expressed were clustered using EXPANDER v5.1software. The regulatory network pathways were identified, and the proteins associated with specific immunotherapy treatment were put into these pathways using Metacore software.
Results A total number of210differential expressed proteins were identified, of which188were significantly associated with allergic rhinitis and91were closely asscociated with allergen specific immunotherapy. Using Metacore pathway software to build10regulatory pathway with the p-value in which the blood coagulation pathway received the smallest P value. The proteins including coagulation factor ⅩⅡ, coagulation factor Ⅲ, F2, alpha-2-macroglobulin and plasminogen of blood coagulation pathway were changed between allergic rhinitis patients, specific immunotherapy-ineffective patients and specific imm- unotherapy-effective patients. In allergic rhinitis group its expression was increased,and in the allergic rhinitis group after specific immunotherapy, the expression of it was decreased in specific immunotherapy effective group and in the specific immunetherapy ineffective group its expression was elevated or did not change significantly. In this study, we also used Metacore software to build the network of transcription factors, the STAT3and STAT1transcription factor network may be closely related to the activation of the coagulation pathways with the highest correlation oefficient.
Conclusion The blood coagulation pathway which consist coagulation factor ⅩⅡ coagulation factor Ⅲ, prothrombin, alpha-2macroglobulin and plasminogen may be an important regulator of the inflammatory response in allergic rhinitis. Specific immunotherapy may reduce the allergic inflammation by inhibiting the activation of coagulation pathways to improve the symptoms of allergic rhinitis. And the coagulation pathway may be acted through STAT3and/or STAT1transcription factor network to regulate the pathogenesis of AR and the activation of the specific immunotherapy.
Charpter2Identication of the expression of Thrombin in serum Allergic Rhinitis patients
Objective Allergic rhinitis is a nasal inflammatory disorders with a high prevalence. The mechanism of the disease has been always in hot discussion, but remains unclear to date. The first chapter have confirmed that the activation and/or inhibition of the blood coagulation pathway might be plays an important roles in the mechanism of inflammatory response of allergic rhinitis and in the efficacy of specific immunotherapy for allergic rhinitis. And in this study we choose the central protein thrombin as the object, detected the expression of it in the surum of allergic rhinitis and specific immunotherapy patients. And try to explore the significance of the thrombin in allergic rhinitis and in specific immunotherapy patients; and then to investigate the correlation of the blood coagulation pathways and allergic rhinitis and the specific immunotherapy
Methods The serum levels thrombin were measured by using enzyme immunoassay in patients with allergic rhinitis (n=20), specific immunotherapy effective patients (n=20) and specific immunotherapy ineffective patients (n=20) compared with those in healthy controls (n=20).
Results Significantly different serum levels of Thrombin were observed among the control group and three patient groups, respectively. Inter-group analysis shows that in patients with allergic rhinitis the expression of thrombin was higher than in controls (P<0.001). And in allergen specific immunotherapy effective patients the expression was lower than allergic rhinitis patients (P<0.001). There was also siginificant difference between allergen specific immunotherapy effective patients and the allergen specific immunotherapy ineffective patients(P<0.001).
Conclusion Thrombin may contribute to the development of allergic rhinitis. Further validated from the point level the coagulation pathway is closely related to allergic rhinitis. The periodic inspect the change of thrombin content in patients with allergic rhinitis may be able to predict the effect of specific immunotherapy and determine the termination time of specific immunotherapy. However, there might be different mechanism underling allergic rhinitis and the allergen specific immunotherapy, for which further studies are still necessary.
目的变应性鼻炎是一种十分常见的疾病,它还是哮喘的高危因素。变应原特异性免疫治疗是唯一可以改变变应性鼻炎疾病进程的治疗方法。然而,变应性鼻炎的发病机制及其特异性免疫治疗的确切机制尚未完全阐明。本研究的目的是为了筛选与常年性变应性鼻炎发病及特异性免疫治疗密切相关的调控因子及其调节网络,为进一步深入研究变应性鼻炎及其免疫治疗的作用机制奠定基础。
方法研究选取了45名确诊为常年性变应性鼻炎患者,22名经特异性免疫治疗有效患者,20名经特异性免疫治疗无效患者及20名健康志愿者作为研究对象。我们对这四组研究对象进行了同位素标记的相对和绝对定量的蛋白组学研究,接着利用二维凝胶电泳及质谱分析确定我们所需的差异蛋白。然后利用利用EXPANDER v5.2软件对这些差异蛋白进行聚类分析。最后将聚类后的差异蛋白汇入Metacore软件,进一步确认可能起重要作用的调节网络及与特异性免疫治疗密切相关的蛋白作用。
结果本研究共确认了210个差异蛋白,其中188个与变应性鼻炎的发生密切相关,91个与特异性免疫治疗的作用相关。通过Metacore通路软件构建了p值最小的10组调节通路,其中以凝血通路的可信度最高。其中参与凝血通路的重要蛋白质如凝血因子XⅡ、凝血因子Ⅲ、凝血酶原、α-2巨球蛋白及纤溶酶原等在四组研究对象中表达都有所改变。在变应性鼻炎组中表达增高,经特异性免疫治疗后,在特异性免疫治疗有效组中其表达下降,而在特异性免疫治疗无效组中其表达升高或变化不明显。在Metacore软件构建的转录因子网络中,STAT3及STAT1转录因子网络与凝血通路的相关系数最高。
结论凝血因子XⅡ、凝血因子Ⅲ、凝血酶原、α-2巨球蛋白及纤溶酶原构成的凝血通路很可能是变应性鼻炎炎症反应的重要调节网络。特异性免疫治疗可能通过抑制凝血通路的活化以减轻变应性炎症反应从而改善变应性鼻炎的症状。而且凝血通路可能通过STAT3和／或STAT1转录因子网络参与AR及特应性免疫治疗的调控。
第二章凝血酶Thrombin在AR血清中的鉴定
目的变应性鼻炎是鼻部常见的慢性炎症性疾病,其发病机制一直以来是基础和临床研究的重点,但至今仍不十分清楚。第一章的研究我们已证实凝血通路的激活和抑制可能对变应性鼻炎的炎症反应和特异性免疫治疗的疗效起着重要作用,本章中我们选择凝血通路中起中心作用的调节因子Thrombin蛋白作为研究对象,检测变应性鼻炎及免疫治疗病人中Thrombin蛋白的表达差异。探讨Thrombin蛋白在变应性鼻炎及特异性免疫治疗中的意义；并检验凝血通路与变应性鼻炎及特异性免疫治疗的相关性。
方法利用酶联免疫吸附法检测变应性鼻炎(20例),特异性免疫治疗有效组患者(20例)及特异性免疫治疗无效组患者(20例)血清中Thrombin蛋白的含量,并与健康志愿者(20例)的结果进行统计学比较。
结果三个病例组(变应性鼻炎、特异性免疫治疗有效组、特异性免疫治疗无效组)与健康对照组总体比较,进一步对血清Thrombin水平进行组间两两比较。结果显示：1、变应性鼻炎组血清中thrombin的含量增高与对照组相比较,两组之间差异有显著统计学意义(P<0.001)。2、在特异性免疫治疗有效组中血清中thrombin的含量显著下降与AR组相比其差异亦具有显著统计学意义(P<0.001)；3、在特异性免疫治疗无效组中血清中thrombin的含量升高或变化不明显与SIT无效组相比较其差异亦具显著性(P<0.001)。
结论Thrombin在变应性鼻炎的发生发展中可能发挥了一定的作用；进一步从点的层面上初步验证了凝血通路与变应性鼻炎密切相关的推论；定期检测患者体内的thrombin含量变化或许能预测特异性免疫治疗的疗效及确定SIT的终止时间。然而Thrombin蛋白在变应性鼻炎中及特异性免疫治疗中的作用机制仍有待于进一步深入研究。
Charpter1The study of serum proteomics and bioinformatics analysis on perennial allergic rhinitis
Objective Allergic rhinitis (AR) is a very common disease and a great risk factor for allergic asthma. Allergen specific immunotherapy is a promising method for changingthe course of allergic rhinitis progression. However, the exact mechanisms of the pathogenesis of allergic rhinitis and the specific immunotherapy have not been fully elucidated. The purposes of this study are to identify the regulatory networks active in perennial allergic rhinitis patients and those receiving specific immunotherapy and then to explore the functions of these regulatory networks. Finally, provide the foundation for the further mechanisms of allergic rhinitis and the specific immunotherapy.
Methods45perennial allergic rhinitis patients,22SIT-effective and20SIT-ineffective allergic rhinitis patients and20healthy controls were recruited for this study. Isobaric tags for relative and absolute quantitation followed by two-dimensional gel electrophoresis and mass spectrometry were used to identify proteins that were differentially expressed among the four groups. The proteins that were significantly differentially expressed were clustered using EXPANDER v5.1software. The regulatory network pathways were identified, and the proteins associated with specific immunotherapy treatment were put into these pathways using Metacore software.
Results A total number of210differential expressed proteins were identified, of which188were significantly associated with allergic rhinitis and91were closely asscociated with allergen specific immunotherapy. Using Metacore pathway software to build10regulatory pathway with the p-value in which the blood coagulation pathway received the smallest P value. The proteins including coagulation factor ⅩⅡ, coagulation factor Ⅲ, F2, alpha-2-macroglobulin and plasminogen of blood coagulation pathway were changed between allergic rhinitis patients, specific immunotherapy-ineffective patients and specific imm- unotherapy-effective patients. In allergic rhinitis group its expression was increased,and in the allergic rhinitis group after specific immunotherapy, the expression of it was decreased in specific immunotherapy effective group and in the specific immunetherapy ineffective group its expression was elevated or did not change significantly. In this study, we also used Metacore software to build the network of transcription factors, the STAT3and STAT1transcription factor network may be closely related to the activation of the coagulation pathways with the highest correlation oefficient.
Conclusion The blood coagulation pathway which consist coagulation factor ⅩⅡ coagulation factor Ⅲ, prothrombin, alpha-2macroglobulin and plasminogen may be an important regulator of the inflammatory response in allergic rhinitis. Specific immunotherapy may reduce the allergic inflammation by inhibiting the activation of coagulation pathways to improve the symptoms of allergic rhinitis. And the coagulation pathway may be acted through STAT3and/or STAT1transcription factor network to regulate the pathogenesis of AR and the activation of the specific immunotherapy.
Charpter2Identication of the expression of Thrombin in serum Allergic Rhinitis patients
Objective Allergic rhinitis is a nasal inflammatory disorders with a high prevalence. The mechanism of the disease has been always in hot discussion, but remains unclear to date. The first chapter have confirmed that the activation and/or inhibition of the blood coagulation pathway might be plays an important roles in the mechanism of inflammatory response of allergic rhinitis and in the efficacy of specific immunotherapy for allergic rhinitis. And in this study we choose the central protein thrombin as the object, detected the expression of it in the surum of allergic rhinitis and specific immunotherapy patients. And try to explore the significance of the thrombin in allergic rhinitis and in specific immunotherapy patients; and then to investigate the correlation of the blood coagulation pathways and allergic rhinitis and the specific immunotherapy
Methods The serum levels thrombin were measured by using enzyme immunoassay in patients with allergic rhinitis (n=20), specific immunotherapy effective patients (n=20) and specific immunotherapy ineffective patients (n=20) compared with those in healthy controls (n=20).
Results Significantly different serum levels of Thrombin were observed among the control group and three patient groups, respectively. Inter-group analysis shows that in patients with allergic rhinitis the expression of thrombin was higher than in controls (P<0.001). And in allergen specific immunotherapy effective patients the expression was lower than allergic rhinitis patients (P<0.001). There was also siginificant difference between allergen specific immunotherapy effective patients and the allergen specific immunotherapy ineffective patients(P<0.001).
Conclusion Thrombin may contribute to the development of allergic rhinitis. Further validated from the point level the coagulation pathway is closely related to allergic rhinitis. The periodic inspect the change of thrombin content in patients with allergic rhinitis may be able to predict the effect of specific immunotherapy and determine the termination time of specific immunotherapy. However, there might be different mechanism underling allergic rhinitis and the allergen specific immunotherapy, for which further studies are still necessary.
引文
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