脑红蛋白及热休克蛋白60在脑挫裂伤病理过程中的作用研究
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摘要
研究背景脑挫裂伤是常见的神经外科疾病,是当今威胁人类生命的主要疾病之一。在医学不断进步的今天,脑挫裂伤的致残、致死率却一直居高不下,至今仍没有一项十分有效的治疗方法。因此,从脑挫裂伤发病机制出发,研究其致病因子对于临床实践十分重要。
脑红蛋白(Neuroglobin, Ngb)是新近发现的一种主要位于神经元内、能够可逆性结合氧的球蛋白,它是一个新的内源性神经保护因子。目前研究表明,Ngb对脑缺血缺氧具有保护作用。热休克蛋白60(Heat Shock Protein60, HSP60)主要定位于细胞线粒体内,生理状态下,HSP60协助细胞多肽或蛋白质正确转位、折叠和装配,当受到不良刺激时,HSP60的表达明显增加,维持细胞内必需蛋白质的空间构象,从而保护细胞生命活动,确保细胞生存。为了探究Ngb及HSP60在脑挫裂伤的病理过程中所起的作用,我们做了一些研究。
本课题共分为三个部分：
第一章脑挫裂伤患者脑组织及血中白细胞差异蛋白质组的表达；
第二章Ngb及HSP60在脑挫裂伤患者脑组织中的表达；
第三章Ngb及HSP60在脑挫裂伤患者血清中的表达。
第一章脑挫裂伤患者脑组织及血中白细胞差异蛋白质组的表达
目的：通过双向凝胶电泳技术建立脑挫裂伤组和正常对照组分辨率高、重复性好的脑组织及血中白细胞蛋白质表达图谱,寻找差异表达的蛋白质点,探讨其功能和作用。
方法：分别采集10例脑挫裂伤患者和10例正常脑组织及血液标本,应用淋巴细胞分离液分离白细胞,再运用二维凝胶电泳技术提取脑组织及白细胞的蛋白质,用PDquest图像分析软件识别差异蛋白质点,MADLI-TOF和生物信息学技术对其进行鉴定和分析。
结果：通过PDQuest7.0分析软件进行点检测,分别获得脑组织及白细胞的蛋白质点数,在脑组织部分：正常组为(764+28)个,脑挫裂伤组(753±19)个。通过和正常对照组进行比较,可发现：脑挫裂伤组中表达上调的蛋白质点有15个,表达下调的蛋白质点有16个。经过与蛋白质数据库比较及质谱技术分析,取9个差异蛋白点进行了鉴定。结果显示,在9个蛋白质点中有7个蛋白质点得到鉴定,它们为硫氧还蛋白(Thioredoxin, Trx),泛素羟基端水解酶L1(Ubiquitin carboxy-terminal hydrolase isozyme L1, UCH-L1),脑红蛋白(Neuroglobin, Ngb), NSFL1辅助因子p47(NSFL1cofactor p47),微管蛋白α链(Microtubulin alpha chain),二氢嘧啶酶相关蛋白2(Dihydropyrimidinase-related protein2),突触小体膜联合25K蛋白(Synaptosomal associated25K protein)。在白细胞部分：正常组为(572±18)个,脑挫裂伤组(518±16)个。与正常组比较分析,脑挫裂伤组中表达上调的蛋白质点有21个,表达下调的蛋白质点有17个。经过与蛋白质数据库比较及质谱技术分析,取9个差异蛋白点进行了鉴定。结果显示,在9个蛋白质点中有6个蛋白质点得到鉴定,它们为钙网织蛋白前体(Calreticulin precursor)、热休克蛋白60(Heat Shock Protein60, HSP60)、钙依赖性蛋白激酶(Calcium-dependent protein kinase)、脂酰辅酶A脱氢酶(Fatty acyl-coa dehydrogenase)、谷氨酸脱氢酶前体(Glutamate dehydrogenase precursor)和醛脱氢酶(Aldehyde dehydrogenase)。结论：1、通过双向凝胶电泳技术初步建立了脑挫裂伤组及正常对照组脑组织及白细胞蛋白质组表达图谱；
2、经过凝胶图像分析,脑挫裂伤组及正常对照组脑组织及白细胞二维凝胶电泳图谱的表达具有明显差异；
3、经过与蛋白质数据库比较及质谱技术分析,鉴定出的差异蛋白质有可能通过细胞分裂、细胞信号传导、蛋白质降解通路、氧化还原反应等参与脑挫裂伤的病理过程,其中Ngb及HSP60在脑挫裂伤的病理过程可能起着重要作用。
第二章脑红蛋白及热休克蛋白60在脑挫裂伤患者脑组织中的表达
目的：应用免疫组织化学方法检测脑挫裂伤患者组及正常对照组脑组织中Ngb及Hsp60的表达,研究Ngb及Hsp60在脑挫裂伤患者组及正常对照组的表达差异,评价Ngb及Hsp60在脑挫裂伤的病理过程的作用。
方法：采用SP法,按照北京中杉金桥生物技术有限公司提供的SP试剂盒说明书进行。本研究切取10例成年脑挫裂伤患者(受伤部位均为右额叶)额叶皮层组织标本,以10例成年脑室肿瘤患者行肿瘤切除术取得的正常额叶皮层组织标本为正常对照。然后按照SP试剂盒说明书进行切片、脱蜡及水化、漂洗及蒸馏水洗涤、微波修复、加入一、二抗孵育、光镜下观察、苏木素衬染、树胶封片、光镜下观察切片染色情况并拍照。
结果：1.免疫组化检测结果显示Ngb表达定位于胞浆内,胞浆内浅棕色物质即为Ngb检测阳性。在正常脑组织中Ngb呈弱阳性表达,脑挫裂伤灶脑组织呈阳性表达；而挫裂伤灶周围接近正常的脑组织中Ngb表达呈强阳性,与正常对照组比较有显著性统计学意义(P<0.05)。
2.免疫组化检测结果显示HSP60表达定位于胞浆内,胞浆内浅棕色物质即为HSP60检测阳性。在正常脑组织中HSP60呈阳性表达,在脑挫裂伤灶脑组织呈阳性表达,而脑挫裂伤灶周围接近正常的脑组织中HSP60表达呈强阳性,与正常对照组比较有显著性统计学意义(P<0.05)。
结论：脑挫裂伤灶周围接近正常的脑组织Ngb及HSP60表达呈强阳性,提示Ngb及HSP60在脑挫裂伤病理过程中发挥了重要作用。
第三章脑红蛋白及热休克蛋白60在脑挫裂伤患者血清中的表达目的：应用免疫印迹方法检测脑挫裂伤患者组及正常对照组血清中Ngb及HSP60的表达,研究Ngb及HSP60在脑挫裂伤患者组及正常对照组血清中的表达差异,评价Ngb及HSP60在脑挫裂伤的病理过程的作用。
方法：参照《现代细胞分子生物学技术》操作。10例脑挫裂伤患者血清均为脑外伤后未经手术治疗患者的血清,正常人血清由年龄和性别匹配的10例志愿者提供。血清样本稀释10倍后,测定蛋白质的浓度,再进行聚丙烯酰胺凝胶电泳,电转移至PVDF膜上,以一抗、二抗孵育,用ECL试剂发光及显影,并以胶中非目的蛋白质条带作为上样量对照。再经扫描获取图像,用图像分析软件确定其灰度值,分析特异蛋白的表达水平。
结果：1.在正常人血清中Ngb呈低表达；脑挫裂伤后3小时血清中Ngb表达升高,在12小时后Ngb达到峰值,其后表达逐渐下降,72小时后Ngb表达恢复至正常。脑挫裂伤后6h及12h Ngb表达与对照组比较有显著性统计学差异(P<0.05).
2.在正常人血清中HSP60呈低表达；脑挫裂伤后3小时血清中HSP60表达升高,直到72小时后才到峰值。脑挫裂伤后24h、48h及72h HSP60表达与对照组比较有显著性统计学差异(P<0.05)。
结论：本章实验结果显示,经免疫印迹检测脑挫裂伤患者血清中Ngb及HSP60的表达增强,与正常对照组比较差异有显著统计学意义,提示Ngb及HSP60在脑挫裂伤病理过程中发挥了重要作用。
综上所述,本研究结论如下：
本系列研究通过蛋白质组学及免疫组化、免疫印迹手段研究脑挫裂伤后人脑组织及血清中蛋白质表达,得出如下结论：
通过蛋白质组学和免疫组化、免疫印迹方法的研究,证明了Ngb和HSP60在脑挫裂伤病理生理过程中发挥着重要作用,Ngb和HSP60可以作为脑挫裂伤血液中的分子标志物；其机制值得进一步深入探讨。
Research background Contusion and laceration of brain is a frequent severe neurosurgical disease. It is one of the principal diseases threatening human life. Though the medical science is more advanced than before, Mutilation and lethality of contusion and laceration of brain is still higher and higher now and there is no extremely effective therapeutic method on these days. So it is very important to follow the pathogenesis of this kind of disease and study the causative agent for the clinical practice. Ngb (Neuroglobin) is a new globin that is situated mainly in neurons and be an endogenous neuroprotector. Being similar to Hgb (Hemoglobin) and Mgb (Myoglobin), Ngb can reversibly combine oxygen. Lots of new researches indicate that Ngb plays a role of neuroprotection in the disease of brain ischemia-hypoxia. Hsp60(Heat Shock Protein60) is situated mainly in mitochondria in cells and help opypeptides or proteins to dislocate, fold and assemble. HSP60also play an important role in the control of the stress. When the bad stimulations come, the expression of HSP60increases immediately, and maintains space conformation of proteins in cells. The vital movement and survival ability of cells is protected accordingly. To study Ngb and HSP60in the pathologic processes of contusion and laceration of brain, we have maken some interesting experiments recently.
There are three parts of my topic:
Chapter one:The expression of different proteome in the brain tissue and blood of the patients with contusion and laceration of brain
Chapter two:The expression of Ngb and HSP60in in the brain tissue of the patients with contusion and laceration of brain
Chpter three:The expression of of Ngb and HSP60in in the serum of the patients with contusion and laceration of brain
Chapter1. The expression of comparative proteome of brain tissue and leukocyte in patients with contusion and laceration of brain
Objective:To establish two-dimensional electrophoresis profiles with high resolution and reproducibility from brain tissue and leucocyte in blood of the patients with contusion and laceration of brain. And to analyse the different expression proteins, investigate the function and effect of them.
Methods:Brain tissue and blood was collected from ten patients with contusion and laceration of brain, eight patients with intraventricular neoplasms who had to be taken operation and ten normal volunteers. The leukocytes were separated from blood by lydroxypropylmethyl cellulose. The proteins in brain tissue and leukocytes were extracted by two-dimensional gel electrophoresis. The image analysis were done using the PDQuest7.0software. The differential protein spots were detected and analyzed with Applied Biosystems Voyager System4307MALDI-TOF Mass Spectrometer and bioinformatical skills.
Results:The proteins were acquired from brain tissue and leukocytes separately and analyzed with the PDQuest7.0software. In the part of brain tissue, there were764±28proteins in the normal group while753±19proteins in the contusion and laceration of brain group. The stained2-DE gels were scanned by Imagescanner. The image analysis were done using the PDQuest7.0software. To compare with the normal group, the expressions of proteins in the contusion and laceration of brain group were different,15spots of proteins were up-regulated while16spots were down-regulated. Part of the spots were detected with the mass spectrum and Protein Databases and seven proteins came out:Trx (Thioredoxin), UCH-L1(Ubiquitin carboxy-terminal hydrolase isozyme L1), Ngb (Neuroglobin), NSFL1cofactor p47, Microtubulin alpha chain, Dihydropyrimidinase-related protein2, Synaptosomal associated25K protein. The proteins were acquired from brain tissue and leukocytes separately and analyzed with the PDQuest7.0software. In the part of leukocyte, there were572±18proteins in the normal group while518±16proteins in the contusion and laceration of brain group. The stained2-DE gels were scanned by Imagescanner. The image analysis were done using the PDQuest7.0software. To compare with the normal group, the expressions of proteins in the contusion and laceration of brain group were different,21spots of proteins were up-regulated while17spots were down-regulated. Part of the spots were detected with the mass spectrum and Protein Databases and six proteins came out:Calreticulin precursor, Hsp60(60kDa Heat shock protein), Aldehyde dehydrogenase Calcium-dependent protein kinase, Fatty acyl-coa dehydrogenase and Glutamate dehydrogenase precursor.
Conclusion:1. We have established the expression maps of brain tissue and leukocytes in the patient with contusion and laceration of brain and the normal group with two-dimensional gel electrophoresis.
2.The differences of the two-dimensional expression maps between the contusion and laceration of brain group and normal group were found after the image analysis of the gels.
3. The proteins with differential expression were detected and analyzed with mass spectrometer and Protein Databases. They could take part in the pathologic processes of contusion and laceration of brain by oxidation-reduction reaction, division of cell and access of protein degradation, signal transduction. Among these proteins, Ngb and Hsp60may play very important roles in the pathologic processes.
Chapter2:The expressions of Ngb and HSP60in the brain tissues of the patients with contusion and laceration of brain
Objective:To detect the expression of Ngb and HSP60in the brain tissue of the patients with contusion and laceration of brain and the normal group with immunohistochemical skills and find the differences between two groups, then to evaluate contributions of Ngb and HSP60in the pathologic process of contusion and laceration of brain.
Methods:Using streptavidin-perosidase (SP) method, according to the directions of the kit supplied from Zhongshan Goldenbridge Biotechnology CO., LTD Beijing. Brain tissues obtained from ten patients with contusion and laceration of brain, all the lesions were at the right lobus frontalis. The normal brain tissues obtained from lobus frontalis of ten patients with brain ventricular neoplasms who had to take operations. Then got slices, deparaffinage and hydration, rinse, wash with distilled water, to repair by microwaves, incubate with first and second antibodys, observe with light microscope, stain with hematoxylin, mount with gum, observe the staining with light microscope and take pictures.
Results:1. Expressions of Ngb were in plasm of cells, the dilute brow object revealed the positive expressions. The expressions of Ngb were weakly positive in normal brain tissues, while it was positive in brain tissues with contusion and laceration and it was hadro-positive in the tissues closed to brain tissues with contusion and laceration. Statistical significant difference could observe between two groups (P<0.05).
2. Expressions of HSP60were in plasm of cells, the dilute brow object revealed the positive expressions. The expressions of HSP60were positive in normal brain tissues, while it was positive in brain tissues with contusion and laceration and it was hadro-positive in the tissues closed to brain tissues with contusion and laceration. Statistical significant difference could be observed between two groups (P<0.05).
Conclusion:The expressions of Ngb and HSP60were hadro-positive in the tissues closed to brain tissues with contusion and laceration. Ngb and HSP60may play important roles in the pathologic process of contusion and laceration of brain.
Chpter three:The expressions of Ngb and HSP60in the serum of the patients with contusion and laceration of brain
Objective:To detect the expression of Ngb and HSP60in serum of the patients with contusion and laceration of brain and the normal group with Western blotting and find the differences between two groups, then to evaluate contributions of Ngb and HSP60in the pathologic process of contusion and laceration of brain.
Methods:There were two groups, one was make up of ten patients with contusion and laceration of brain who had not taken operation, another was make up of ten volunteers. The sample of serum was diluted, concentration of proteins were detected, then polyacrylamide gel electrophoresis was taken, transfer to PVDF membranes, incubate with first and second antibodys, luminescence and developing with ECL reagent. Get image after scan, software of image analysis, to detect gray scale, then analize the special protein.
Results:1. Expressions of Ngb were low in normal serum; Expressions of Ngb up-regulated three hours after contusion and laceration, peak of the expression appeared at12hours after contusion and laceration and the expressions down-regulated then, Ngb became normal at72hours after contusion and laceration. Statistical significant difference could be observed between the two groups at6h and12h after contusion and laceration (P<0.05).
2. Expressions of HSP60were low in normal serum; Expressions of Ngb up-regulated three hours after contusion and laceration, peak of the expression appeared at72hours after contusion and laceration. Statistical significant difference could be observed between the two groups at24h,48h and72h after contusion and laceration (P<0.05).
Conclusion:The expressions of Ngb and HSP60were hadro-positive in the serum of patients with contusion and laceration, Statistical significant difference could be observed between normal group and patients. Ngb and HSP60may play important roles in the pathologic process of contusion and laceration of brain.
脑红蛋白(Neuroglobin, Ngb)是新近发现的一种主要位于神经元内、能够可逆性结合氧的球蛋白,它是一个新的内源性神经保护因子。目前研究表明,Ngb对脑缺血缺氧具有保护作用。热休克蛋白60(Heat Shock Protein60, HSP60)主要定位于细胞线粒体内,生理状态下,HSP60协助细胞多肽或蛋白质正确转位、折叠和装配,当受到不良刺激时,HSP60的表达明显增加,维持细胞内必需蛋白质的空间构象,从而保护细胞生命活动,确保细胞生存。为了探究Ngb及HSP60在脑挫裂伤的病理过程中所起的作用,我们做了一些研究。
本课题共分为三个部分：
第一章脑挫裂伤患者脑组织及血中白细胞差异蛋白质组的表达；
第二章Ngb及HSP60在脑挫裂伤患者脑组织中的表达；
第三章Ngb及HSP60在脑挫裂伤患者血清中的表达。
第一章脑挫裂伤患者脑组织及血中白细胞差异蛋白质组的表达
目的：通过双向凝胶电泳技术建立脑挫裂伤组和正常对照组分辨率高、重复性好的脑组织及血中白细胞蛋白质表达图谱,寻找差异表达的蛋白质点,探讨其功能和作用。
方法：分别采集10例脑挫裂伤患者和10例正常脑组织及血液标本,应用淋巴细胞分离液分离白细胞,再运用二维凝胶电泳技术提取脑组织及白细胞的蛋白质,用PDquest图像分析软件识别差异蛋白质点,MADLI-TOF和生物信息学技术对其进行鉴定和分析。
结果：通过PDQuest7.0分析软件进行点检测,分别获得脑组织及白细胞的蛋白质点数,在脑组织部分：正常组为(764+28)个,脑挫裂伤组(753±19)个。通过和正常对照组进行比较,可发现：脑挫裂伤组中表达上调的蛋白质点有15个,表达下调的蛋白质点有16个。经过与蛋白质数据库比较及质谱技术分析,取9个差异蛋白点进行了鉴定。结果显示,在9个蛋白质点中有7个蛋白质点得到鉴定,它们为硫氧还蛋白(Thioredoxin, Trx),泛素羟基端水解酶L1(Ubiquitin carboxy-terminal hydrolase isozyme L1, UCH-L1),脑红蛋白(Neuroglobin, Ngb), NSFL1辅助因子p47(NSFL1cofactor p47),微管蛋白α链(Microtubulin alpha chain),二氢嘧啶酶相关蛋白2(Dihydropyrimidinase-related protein2),突触小体膜联合25K蛋白(Synaptosomal associated25K protein)。在白细胞部分：正常组为(572±18)个,脑挫裂伤组(518±16)个。与正常组比较分析,脑挫裂伤组中表达上调的蛋白质点有21个,表达下调的蛋白质点有17个。经过与蛋白质数据库比较及质谱技术分析,取9个差异蛋白点进行了鉴定。结果显示,在9个蛋白质点中有6个蛋白质点得到鉴定,它们为钙网织蛋白前体(Calreticulin precursor)、热休克蛋白60(Heat Shock Protein60, HSP60)、钙依赖性蛋白激酶(Calcium-dependent protein kinase)、脂酰辅酶A脱氢酶(Fatty acyl-coa dehydrogenase)、谷氨酸脱氢酶前体(Glutamate dehydrogenase precursor)和醛脱氢酶(Aldehyde dehydrogenase)。结论：1、通过双向凝胶电泳技术初步建立了脑挫裂伤组及正常对照组脑组织及白细胞蛋白质组表达图谱；
2、经过凝胶图像分析,脑挫裂伤组及正常对照组脑组织及白细胞二维凝胶电泳图谱的表达具有明显差异；
3、经过与蛋白质数据库比较及质谱技术分析,鉴定出的差异蛋白质有可能通过细胞分裂、细胞信号传导、蛋白质降解通路、氧化还原反应等参与脑挫裂伤的病理过程,其中Ngb及HSP60在脑挫裂伤的病理过程可能起着重要作用。
第二章脑红蛋白及热休克蛋白60在脑挫裂伤患者脑组织中的表达
目的：应用免疫组织化学方法检测脑挫裂伤患者组及正常对照组脑组织中Ngb及Hsp60的表达,研究Ngb及Hsp60在脑挫裂伤患者组及正常对照组的表达差异,评价Ngb及Hsp60在脑挫裂伤的病理过程的作用。
方法：采用SP法,按照北京中杉金桥生物技术有限公司提供的SP试剂盒说明书进行。本研究切取10例成年脑挫裂伤患者(受伤部位均为右额叶)额叶皮层组织标本,以10例成年脑室肿瘤患者行肿瘤切除术取得的正常额叶皮层组织标本为正常对照。然后按照SP试剂盒说明书进行切片、脱蜡及水化、漂洗及蒸馏水洗涤、微波修复、加入一、二抗孵育、光镜下观察、苏木素衬染、树胶封片、光镜下观察切片染色情况并拍照。
结果：1.免疫组化检测结果显示Ngb表达定位于胞浆内,胞浆内浅棕色物质即为Ngb检测阳性。在正常脑组织中Ngb呈弱阳性表达,脑挫裂伤灶脑组织呈阳性表达；而挫裂伤灶周围接近正常的脑组织中Ngb表达呈强阳性,与正常对照组比较有显著性统计学意义(P<0.05)。
2.免疫组化检测结果显示HSP60表达定位于胞浆内,胞浆内浅棕色物质即为HSP60检测阳性。在正常脑组织中HSP60呈阳性表达,在脑挫裂伤灶脑组织呈阳性表达,而脑挫裂伤灶周围接近正常的脑组织中HSP60表达呈强阳性,与正常对照组比较有显著性统计学意义(P<0.05)。
结论：脑挫裂伤灶周围接近正常的脑组织Ngb及HSP60表达呈强阳性,提示Ngb及HSP60在脑挫裂伤病理过程中发挥了重要作用。
第三章脑红蛋白及热休克蛋白60在脑挫裂伤患者血清中的表达目的：应用免疫印迹方法检测脑挫裂伤患者组及正常对照组血清中Ngb及HSP60的表达,研究Ngb及HSP60在脑挫裂伤患者组及正常对照组血清中的表达差异,评价Ngb及HSP60在脑挫裂伤的病理过程的作用。
方法：参照《现代细胞分子生物学技术》操作。10例脑挫裂伤患者血清均为脑外伤后未经手术治疗患者的血清,正常人血清由年龄和性别匹配的10例志愿者提供。血清样本稀释10倍后,测定蛋白质的浓度,再进行聚丙烯酰胺凝胶电泳,电转移至PVDF膜上,以一抗、二抗孵育,用ECL试剂发光及显影,并以胶中非目的蛋白质条带作为上样量对照。再经扫描获取图像,用图像分析软件确定其灰度值,分析特异蛋白的表达水平。
结果：1.在正常人血清中Ngb呈低表达；脑挫裂伤后3小时血清中Ngb表达升高,在12小时后Ngb达到峰值,其后表达逐渐下降,72小时后Ngb表达恢复至正常。脑挫裂伤后6h及12h Ngb表达与对照组比较有显著性统计学差异(P<0.05).
2.在正常人血清中HSP60呈低表达；脑挫裂伤后3小时血清中HSP60表达升高,直到72小时后才到峰值。脑挫裂伤后24h、48h及72h HSP60表达与对照组比较有显著性统计学差异(P<0.05)。
结论：本章实验结果显示,经免疫印迹检测脑挫裂伤患者血清中Ngb及HSP60的表达增强,与正常对照组比较差异有显著统计学意义,提示Ngb及HSP60在脑挫裂伤病理过程中发挥了重要作用。
综上所述,本研究结论如下：
本系列研究通过蛋白质组学及免疫组化、免疫印迹手段研究脑挫裂伤后人脑组织及血清中蛋白质表达,得出如下结论：
通过蛋白质组学和免疫组化、免疫印迹方法的研究,证明了Ngb和HSP60在脑挫裂伤病理生理过程中发挥着重要作用,Ngb和HSP60可以作为脑挫裂伤血液中的分子标志物；其机制值得进一步深入探讨。
Research background Contusion and laceration of brain is a frequent severe neurosurgical disease. It is one of the principal diseases threatening human life. Though the medical science is more advanced than before, Mutilation and lethality of contusion and laceration of brain is still higher and higher now and there is no extremely effective therapeutic method on these days. So it is very important to follow the pathogenesis of this kind of disease and study the causative agent for the clinical practice. Ngb (Neuroglobin) is a new globin that is situated mainly in neurons and be an endogenous neuroprotector. Being similar to Hgb (Hemoglobin) and Mgb (Myoglobin), Ngb can reversibly combine oxygen. Lots of new researches indicate that Ngb plays a role of neuroprotection in the disease of brain ischemia-hypoxia. Hsp60(Heat Shock Protein60) is situated mainly in mitochondria in cells and help opypeptides or proteins to dislocate, fold and assemble. HSP60also play an important role in the control of the stress. When the bad stimulations come, the expression of HSP60increases immediately, and maintains space conformation of proteins in cells. The vital movement and survival ability of cells is protected accordingly. To study Ngb and HSP60in the pathologic processes of contusion and laceration of brain, we have maken some interesting experiments recently.
There are three parts of my topic:
Chapter one:The expression of different proteome in the brain tissue and blood of the patients with contusion and laceration of brain
Chapter two:The expression of Ngb and HSP60in in the brain tissue of the patients with contusion and laceration of brain
Chpter three:The expression of of Ngb and HSP60in in the serum of the patients with contusion and laceration of brain
Chapter1. The expression of comparative proteome of brain tissue and leukocyte in patients with contusion and laceration of brain
Objective:To establish two-dimensional electrophoresis profiles with high resolution and reproducibility from brain tissue and leucocyte in blood of the patients with contusion and laceration of brain. And to analyse the different expression proteins, investigate the function and effect of them.
Methods:Brain tissue and blood was collected from ten patients with contusion and laceration of brain, eight patients with intraventricular neoplasms who had to be taken operation and ten normal volunteers. The leukocytes were separated from blood by lydroxypropylmethyl cellulose. The proteins in brain tissue and leukocytes were extracted by two-dimensional gel electrophoresis. The image analysis were done using the PDQuest7.0software. The differential protein spots were detected and analyzed with Applied Biosystems Voyager System4307MALDI-TOF Mass Spectrometer and bioinformatical skills.
Results:The proteins were acquired from brain tissue and leukocytes separately and analyzed with the PDQuest7.0software. In the part of brain tissue, there were764±28proteins in the normal group while753±19proteins in the contusion and laceration of brain group. The stained2-DE gels were scanned by Imagescanner. The image analysis were done using the PDQuest7.0software. To compare with the normal group, the expressions of proteins in the contusion and laceration of brain group were different,15spots of proteins were up-regulated while16spots were down-regulated. Part of the spots were detected with the mass spectrum and Protein Databases and seven proteins came out:Trx (Thioredoxin), UCH-L1(Ubiquitin carboxy-terminal hydrolase isozyme L1), Ngb (Neuroglobin), NSFL1cofactor p47, Microtubulin alpha chain, Dihydropyrimidinase-related protein2, Synaptosomal associated25K protein. The proteins were acquired from brain tissue and leukocytes separately and analyzed with the PDQuest7.0software. In the part of leukocyte, there were572±18proteins in the normal group while518±16proteins in the contusion and laceration of brain group. The stained2-DE gels were scanned by Imagescanner. The image analysis were done using the PDQuest7.0software. To compare with the normal group, the expressions of proteins in the contusion and laceration of brain group were different,21spots of proteins were up-regulated while17spots were down-regulated. Part of the spots were detected with the mass spectrum and Protein Databases and six proteins came out:Calreticulin precursor, Hsp60(60kDa Heat shock protein), Aldehyde dehydrogenase Calcium-dependent protein kinase, Fatty acyl-coa dehydrogenase and Glutamate dehydrogenase precursor.
Conclusion:1. We have established the expression maps of brain tissue and leukocytes in the patient with contusion and laceration of brain and the normal group with two-dimensional gel electrophoresis.
2.The differences of the two-dimensional expression maps between the contusion and laceration of brain group and normal group were found after the image analysis of the gels.
3. The proteins with differential expression were detected and analyzed with mass spectrometer and Protein Databases. They could take part in the pathologic processes of contusion and laceration of brain by oxidation-reduction reaction, division of cell and access of protein degradation, signal transduction. Among these proteins, Ngb and Hsp60may play very important roles in the pathologic processes.
Chapter2:The expressions of Ngb and HSP60in the brain tissues of the patients with contusion and laceration of brain
Objective:To detect the expression of Ngb and HSP60in the brain tissue of the patients with contusion and laceration of brain and the normal group with immunohistochemical skills and find the differences between two groups, then to evaluate contributions of Ngb and HSP60in the pathologic process of contusion and laceration of brain.
Methods:Using streptavidin-perosidase (SP) method, according to the directions of the kit supplied from Zhongshan Goldenbridge Biotechnology CO., LTD Beijing. Brain tissues obtained from ten patients with contusion and laceration of brain, all the lesions were at the right lobus frontalis. The normal brain tissues obtained from lobus frontalis of ten patients with brain ventricular neoplasms who had to take operations. Then got slices, deparaffinage and hydration, rinse, wash with distilled water, to repair by microwaves, incubate with first and second antibodys, observe with light microscope, stain with hematoxylin, mount with gum, observe the staining with light microscope and take pictures.
Results:1. Expressions of Ngb were in plasm of cells, the dilute brow object revealed the positive expressions. The expressions of Ngb were weakly positive in normal brain tissues, while it was positive in brain tissues with contusion and laceration and it was hadro-positive in the tissues closed to brain tissues with contusion and laceration. Statistical significant difference could observe between two groups (P<0.05).
2. Expressions of HSP60were in plasm of cells, the dilute brow object revealed the positive expressions. The expressions of HSP60were positive in normal brain tissues, while it was positive in brain tissues with contusion and laceration and it was hadro-positive in the tissues closed to brain tissues with contusion and laceration. Statistical significant difference could be observed between two groups (P<0.05).
Conclusion:The expressions of Ngb and HSP60were hadro-positive in the tissues closed to brain tissues with contusion and laceration. Ngb and HSP60may play important roles in the pathologic process of contusion and laceration of brain.
Chpter three:The expressions of Ngb and HSP60in the serum of the patients with contusion and laceration of brain
Objective:To detect the expression of Ngb and HSP60in serum of the patients with contusion and laceration of brain and the normal group with Western blotting and find the differences between two groups, then to evaluate contributions of Ngb and HSP60in the pathologic process of contusion and laceration of brain.
Methods:There were two groups, one was make up of ten patients with contusion and laceration of brain who had not taken operation, another was make up of ten volunteers. The sample of serum was diluted, concentration of proteins were detected, then polyacrylamide gel electrophoresis was taken, transfer to PVDF membranes, incubate with first and second antibodys, luminescence and developing with ECL reagent. Get image after scan, software of image analysis, to detect gray scale, then analize the special protein.
Results:1. Expressions of Ngb were low in normal serum; Expressions of Ngb up-regulated three hours after contusion and laceration, peak of the expression appeared at12hours after contusion and laceration and the expressions down-regulated then, Ngb became normal at72hours after contusion and laceration. Statistical significant difference could be observed between the two groups at6h and12h after contusion and laceration (P<0.05).
2. Expressions of HSP60were low in normal serum; Expressions of Ngb up-regulated three hours after contusion and laceration, peak of the expression appeared at72hours after contusion and laceration. Statistical significant difference could be observed between the two groups at24h,48h and72h after contusion and laceration (P<0.05).
Conclusion:The expressions of Ngb and HSP60were hadro-positive in the serum of patients with contusion and laceration, Statistical significant difference could be observed between normal group and patients. Ngb and HSP60may play important roles in the pathologic process of contusion and laceration of brain.
引文
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