CN117925819A - Synj1蛋白标记物在制备用于抑郁症辅助诊断的试剂盒中的应用 - Google Patents
Synj1蛋白标记物在制备用于抑郁症辅助诊断的试剂盒中的应用 Download PDFInfo
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Abstract
本发明公开了一种SYNJ1蛋白标记物在制备用于抑郁症辅助诊断的试剂盒中的应用。本发明采用PCR实验、蛋白免疫印迹实验的方法显示出抑郁症群体、非抑郁症群体以及经药物治疗后的抑郁症群体中表达具有显著差异的特定蛋白SYNJ1的标志物,此SYNJ1蛋白标志物将为抑郁症患者提供了一种新的标记物在辅助诊断的试剂盒的应用及其试剂盒。
Description
技术领域
本发明涉及生物医药技术领域。更具体地说,本发明涉及一种SYNJ1蛋白标记物在制备用于抑郁症辅助诊断的试剂盒中的应用。
背景技术
抑郁症是以显著、持续的情绪低落和快感缺失为主要临床特征的一种精神障碍,是目前患病率最高的精神疾病。世界卫生组织(WHO)最新发布的数据显示,全球抑郁患者数量超过3亿,且抑郁症具有高复发率、高自杀率的特点,患病群体趋于年轻化,常与焦虑共发,诱发免疫、内分泌、消化、心血管等多系统功能紊乱,已成为世界范围内的首要致残原因。
目前抑郁症的发病机制并未明确解析,抑郁症的发生有多个生物学假说,包括单胺能神经递质假说、脑奖赏通路受损假说、下丘脑-垂体-肾上腺素轴(HPA轴)功能异常假说及神经营养因子假说等,从而导致抑郁症治疗可选的药物靶点及有效的治疗药物非常有限。
Synaptojanin 1(SYNJ1)是一种调节神经元内分泌途径和神经瘤的蛋白,是维持突触活性所必需的。最近SYNJ1被报道为唐氏综合征、帕金森病和阿尔茨海默氏病的候选基因,研究称其在突触的囊泡回收和脂质代谢中发挥重要作用,但SYNJ1在抑郁症中的作用未见报道。
发明内容
本发明的一个目的是解决至少上述问题,并提供至少后面将说明的优点。
为了实现根据本发明的这些目的和其它优点,提供了一种SYNJ1蛋白标记物在制备用于待检测对象抑郁症辅助诊断的试剂盒中的应用。
优选的是,所述抑郁症包括内源性抑郁症、反应性抑郁症、隐匿性抑郁症、药物引起的继发性抑郁症、更年期抑郁症、产后抑郁症、脑外伤诱发的抑郁症、脑卒中诱发的抑郁症或抑郁性神经症。
提供一种所述的SYNJ1蛋白标记物制备得到的用于待检测对象抑郁症辅助诊断的试剂盒。
本发明至少包括以下有益效果:本发明采用PCR实验、蛋白免疫印迹实验的方法显示出抑郁症群体、非抑郁症群体以及经药物治疗后的抑郁症群体中表达具有显著差异的特定蛋白SYNJ1的标志物,此SYNJ1蛋白标志物将为抑郁症患者提供了一种新的标记物在辅助诊断的试剂盒的应用及其试剂盒,也为进一步阐明此类疾病的病理机制奠定基础。
本发明的其它优点、目标和特征将部分通过下面的说明体现,部分还将通过对本发明的研究和实践而为本领域的技术人员所理解。
附图说明
图1为发明其中一个实施例中的差异性基因的热图;
图2为发明其中一个实施例中的差异性基因的火山图;
图3为发明其中一个实施例中的各组大鼠的蔗糖偏好指数图;
图4为发明其中一个实施例中的各组大鼠的穿格次数图;
图5为发明其中一个实施例中的各组大鼠的直立次数图;
图6为发明其中一个实施例中的各组大鼠运动的总距离图;
图7为发明其中一个实施例中的各组大鼠的摄食潜伏期图;
图8为发明其中一个实施例中的各组大鼠在5min内的不动时间图;
图9为发明其中一个实施例中的SYNJ1的溶解曲线;
图10为发明其中一个实施例中的GAPDH的溶解曲线;
图11为发明其中一个实施例中的SYNJ1的蛋白免疫印迹检测结果图;
图12为发明其中一个实施例中的空白对照组和模型组的SYNJ1蛋白的相对表达水平;
图13为发明其中一个实施例中的空白对照组、模型组以及给药组的SYNJ1基因的相对表达水平。
具体实施方式
下面结合实施例对本发明做进一步的详细说明,以令本领域技术人员参照说明书文字能够据以实施。
需要说明的是,下述实施方案中所述实验方法,如无特殊说明,均为常规方法,所述试剂和材料,如无特殊说明,均可从商业途径获得。
实验动物:SPF级(无特定病原体动物)野生型和BCAT1(转氨酶)敲除的SD大鼠,雄性,体重140~160g,5周龄,购自赛业生物科技有限公司,动物实验遵守国际实验动物伦理学要求;
实验材料:所述试剂和材料,如无特殊说明,均可从商业途径获得,其中,10×KingRT缓冲液、FastKing RT Enzyme Mix、FQ-RT Primer Mix、SYBR Green Master Mix均购自天根生化科技有限公司,RIPA裂解液、磷酸酶抑制剂、蛋白酶抑制剂、10%APS、TEMED均购自美国Sigma公司,BCA蛋白定量试剂盒购自美国Thermo fisher Scientific公司,30%Acrylamide制胶液购自北京索莱宝科技有限公司,Tris-HCl购自北京普利莱基因技术有限公司,10%SDS购自上海碧云天生物技术有限公司,蛋白marker标志物购自Thermo fisherScientific生物公司。
一、差异蛋白筛选
随机选取来自GSE54568队列的15例重度抑郁和15例正常对照样本。在FDR<0.05的筛选条件下,筛选出1419个基因差异表达,其中,基因差异表达的热图和火山图(根据FDR排序)分别如图1和图2所示,结果筛选出CYP46A1、ARF1、MDH1、BCAT1、UQCRH、PRKAR1A、CACNA1E、HMGCS1、EIF4A2、OSBPL3、HACD3、SNRPN、SYNJ1等17个基因为候选的差异蛋白。
<实施例1>
建立抑郁症模型
SD大鼠购入后适应性饲养4天,随机分为空白对照组和模型组。由于机体对单一应激原的刺激易产生耐受性,因此,本实验对模型组的大鼠采用多种不可预知的刺激方式交替进行,建立大鼠慢性不可预知温和应激CUMS模型。慢性应激时程共计4周,应激方式如下:(1)食物剥夺(禁食)、(2)禁水、(3)频闪、(4)通宵照明、(5)潮湿饲养(200mL水加到150g垫料)、(6)冷水游泳(水温l0℃)、(7)倾斜饲养(倾斜45°)、(8)夹尾(距尾根1cm夹闭)2min、(9)制动1~2h、(10)拥挤饲养7h(7只/笼),以上应激方式每天随机使用一种,但禁水、禁食隔开进行。
4周慢性应激结束后进行行为学测试,具体为:于28天进行蔗糖饮水实验,30天进行旷场实验,32天进行新奇抑制摄食实验,33天进行强迫游泳实验评价CUMS大鼠动物模型。
1.1蔗糖偏好测试
测试前24h在空白对照组和模型组中均放入两瓶1%(w/v)的蔗糖溶液,24h后将其中的一瓶换成纯水,进行适应训练。适应结束后,给予48h正常饮食饮水,后禁食禁水14h,基线测试1h。重复3次,测定3次糖水基线,称重,记录各组大鼠的总液体消耗、糖水消耗和纯水消耗,并计算平均每只大鼠的糖水偏好指数,其中,糖水偏好指数计算公式为:
空白对照组和模型组的蔗糖偏好测试结果如图1所示,根据图3数据可知,CUMS造模第28天,与空白对照组相比,模型组大鼠的蔗糖偏好指数显著降低(P<0.001),表明模型组大鼠出现快感缺失样症状。
1.2旷场实验
旷场实验仪器为一个长宽高均为100cm的开阔敞箱,底面分为9个等面积的个小方格,实验时将空白对照组和模型组的大鼠分别从开敞箱的同一方向、同一位置放入,观察其5min内的活动,统计各组大鼠的运动总距离、跨格次数和直立次数等,注意实验测试环境应尽量保持安静,每次实验后均需清理动物粪便并消毒,其中,跨格数统计标准为至少3个爪跨过边界,直立次数统计标准为两前爪离开地面。
空白对照组和模型组的旷场实验结果如图4~6所示,根据图4~6数据可知,CUMS造模第31天,与空白对照组相比,模型组大鼠在旷场实验中的穿格次数(P<0.001)、直立次数(P<0.001)和运动总距离(P<0.001)显著降低,表明模型组大鼠的自发活动减少。
1.3新奇抑制摄食实验
测试前将空白对照组和模型组大鼠均禁食48h,测试时将各组大鼠放入陌生空旷室内角落的地板上,划定并包围100×100×100cm的场地作为大鼠活动范围,在划定场地的中央放置6~8粒饲料,测试开始后让大鼠自由探索5min。记录5min内各组大鼠开始进食饲料的潜伏期,其中,潜伏期判断标准为:从大鼠放入场地到开始咀嚼饲料的时间间隔(嗅食和摆弄饲料除外)。
空白对照组和模型组的旷场实验结果如图7所示,根据图7数据可知,CUMS造模第32天,与空白对照组相比,模型组大鼠在新奇环境中的摄食潜伏期(P<0.001)显著增加。
1.3强迫游泳实验
将将各组大鼠分别置于一个直径20cm、高度40cm含水的圆柱形玻璃缸中,水深30cm,水温25℃,记录大鼠放入5min内的累计不动时间,其中,当大鼠进入漂浮姿态,停止挣扎,且头部高于水时被认定为不动状态,实验时环境应保持绝对安静,且每只测完后均需要更换25℃的干净水。
空白对照组和模型组的旷场实验结果如图8所示,根据图8数据可知,CUMS造模第33天,与空白对照组相比,模型组大鼠在强迫游泳实验中5min内的不动时间显著增加(P<0.001),表明大鼠在不可逃避的环境中的绝望程度加重。
根据图3~8的数据可知,CUMS造模后大鼠出现了抑郁样症状,表明CUMS大鼠抑郁模型成功建立,CUMS模型的建立引起动物缺乏快感,且该抑郁模型具有效性和持续性,表明造模效果良好,可用于进行后续实验。
二、灌胃给药和样本采集
2.1灌胃给药
模型组大鼠模型建立4周后,从模型组种随机分出一半大鼠作为给药组,给药组灌胃给予氟西汀(10mg/kg),剩余的模型组和空白对照组同时灌胃等体积的生理盐水,一天灌胃一次,连续灌胃5周。
2.2样本采集
各组大鼠麻醉后取出脑组织,去除多余脑组织,分离出左右两侧的前额叶皮质部分,置于液氮速冻后保存。
三、筛选基因差异性表达的PCR实验
3.1RNA提取
提取RNA所用实验台预先消毒后,分别取空白对照组、模型组动物的前额叶皮质组织(每份<50mg)放入含1mL RNA抽取试剂(Trizol试剂)的EP管中,匀浆,冰上静置5min,得到匀浆液,向匀浆组织液中加入0.2mL氯仿(其中,氯仿:Trizol=1:5),用力快速振摇20s,冰上静置10min后,于4℃下12000rpm离心15min,结束后可见体系分为三层(上层为水相,中间为蛋白质,下层为有机相),吸取上层水相(0.4mL),移入新EP管,加入与吸取的上清水相等体积的异丙醇0.4mL,轻摇混合均匀,冰上静置10min使RNA沉淀后,放入低温快速离心机中,于4℃下12000rpm离心10min,去除上清,再加入1mL75%的乙醇(高效去离子水和无水乙醇配制)洗涤EP管壁,于4℃下12000rpm离心5min,弃上清,获管底附着的凝胶样物质,两次重复上步骤后,将EP管静置风干5~10min,加入10μL高效去离子水(DEPC水)溶解附着在管壁的RNA,得到RNA样品溶液。
3.2RNA含量测定
吸取各组1μL的RNA样品溶液,测定260nm和280nm波长下的吸光度值,并计算其浓度,其中,各组RNA溶液的OD260/OD280大于1.8小于2.1为宜。
3.3逆转录实验
(1)去除基因组DNA
分别取各组1000ng RNA按照下表1所示配制形成RNA体系溶液(冰上操作),其中,RNase-Free ddH2O是指用DEPC即焦碳酸二乙酯处理过并经高温高压灭菌的双蒸水:
表1 RNA配制体系
成分 | 体积(μL) |
5×gDNA缓冲液 | 2 |
总RNA | 根据RNA溶液浓度计算1000ng所需的体积X |
RNase-Free ddH2O | 10-2-X |
混匀后离心,置于PCR仪中42℃孵育3min,取出置于冰上进行下一步;
(2)按照下表2所示,配制逆转录反应体系的反应液(冰上操作);
表2逆转录反应体系
成分 | 体积(μL) |
10×King RT缓冲液 | 2 |
FastKing RT Enzyme Mix | 1 |
FQ-RT Primer Mix | 2 |
RNase-Free ddH2O | 5 |
(3)将(2)中配置的反应液加入到(1)中的RNA体系溶液中,混匀;
(4)将混匀后的溶液放入PCR仪中,设置程序为42℃,15min;95℃,3min,12℃,+∞。
(5)得到的cDNA用于下一步或-20℃保存。
3.4PCR反应
将储存在-20℃各组的cDNA样品和引物提前放在冰上解冻,涡旋离心后备用。根据引物说明书提前将引物稀释完成,在八连排小管中参照下表3所示,建立总体积为20μL的PCR反应体系,放入PCR仪设置参数进行反应,打开程序文件后进行扩增,引物序列见下表4,内参选用GAPDH,引物购自青岛蔚来生物科技有限公司,其中,图9为SYNJ1的熔解曲线,曲线显示为单峰,表明引物具有较强特异性,其Tm值即DNA解链50%的温度约为83℃,图10为GAPDH的熔解曲线,曲线显示为单峰,表明引物具有较强特异性,其Tm值,即DNA解链50%的温度约为85℃。
表3 PCR反应体系
名称 | 体积(μL) |
SYBR Green Master Mix | 10 |
cDNA样品 | 1 |
前引物 | 0.6 |
后引物 | 0.6 |
ddH2O | 7.8 |
总体积 | 20 |
表4引物序列表
3.5实验结果
测定两组大鼠组织内的各个候选基因的相对表达量(取各组大鼠的平均值),其数值如下表5所示:
表5各个候选基因的相对表达量
基因 | 空白对照组 | 模型组 |
CYP46A1 | 1.15 | 1.13 |
ARF1 | 0.98 | 0.97 |
MDH1 | 0.95 | 1.17 |
BCAT1 | 0.94 | 0.79 |
UQCRH | 0.81 | 0.80 |
PRKAR1A | 0.86 | 0.80 |
CACNA1E | 0.89 | 0.62 |
HMGCS1 | 4.51 | 8.32 |
EIF4A2 | 0.80 | 0.79 |
OSBPL3 | 0.78 | 0.77 |
HACD3 | 1.15 | 1.31 |
SNRPN | 2.51 | 4.63 |
KLF3 | 1.12 | 1.42 |
HNRNPK | 1.23 | 1.45 |
SRSF7 | 0.41 | 0.17 |
OVOL2 | 0.38 | 0.02 |
SYNJ1 | 2.31 | 16.02 |
根据表5数据可知,与空白对照组大鼠相比,只有模型组大鼠前额叶皮质中的SYNJ1基因表达水平显著增加(P<0.01),确定SYNJ1为标记基因。
四、蛋白免疫印迹实验
3.1组织裂解和蛋白提取
取出空白对照组和模型组-80℃保存的前额叶组织后,称量,并分别加入裂解液(100mg组织中含1mL RIPA裂解液、4μL磷酸酶抑制剂和4μL蛋白酶抑制剂),向盛有组织和裂解液离心管中加入3~5颗匀浆珠,匀浆(匀浆仪设置:匀浆3次,每次持续6s,间隔5s),匀浆完成后冰上静置30min,随后放入低温高速离心机离心10min,转速12000rpm,温度4℃。吸取上清,上清液即为提取出的蛋白原液。
3.2蛋白浓度测定
向5μL蛋白原液中加入95μL蒸馏水混合,将蛋白原液稀释20倍作为样品溶液进行定量。将BCA蛋白定量试剂盒中的蛋白标准品用蒸馏水依次稀释为2、1.5、1.0、0.75、0.5、0.25、0.125、0.025μg/μL的浓度,再将BCA蛋白定量试剂盒中的A液和B液配制成工作液(A:B=50:1),向96孔板中加入配制好的不同浓度的标准品及各样品溶液20μL,每个浓度标准品和样品溶液重复加入3次,随后向每个孔中快速加入200μL配制好的工作液,缓慢振荡30s混匀,用锡纸覆盖好进行避光后,移入37℃孵育箱孵育30min,孵育结束后,放置入酶标仪进行浓度测定,波长设置在562nm处读取各吸光度值,随后建立标准曲线计算出稀释20倍后的样品溶液浓度,从而确定出蛋白原液浓度。
3.3蛋白变性
吸取各组蛋白原液400μL转移入新EP管中,加入100μL蛋白上样缓冲液,充分混匀,得到蛋白样品,100℃金属浴加热5min,待冷却恢复室温后放入-20℃保存。
3.4PAGE凝胶制备
清洗干净玻璃胶板,放于50℃烘干箱内烘干;
3.4.1分离胶配制
按照说明书所给比例向EP管中依次加入蒸馏水、30%Acrylamide制胶液、1.5MTris-HCl(pH=8.8)、10%SDS(十二烷基磺酸钠)溶液和10%APS(硫酸铵),最后加入TEMED(四甲基乙二胺)后充分混匀,用胶头滴管快速加至胶板内(避免有气泡),再沿胶板从左到右均匀加入无水乙醇压平,室温静置至凝固,即可得到分离胶。
3.4.2配制浓缩胶
分离胶静置过程中,配制浓缩胶。按照说明书所给浓缩胶比例向另一EP管中依次加入蒸馏水、30%Acrylamide制胶液、1.5M Tris-HCl(pH=6.8)、10%SDS和10%APS,得到混合液,向预先配制比好的混合液中加入TEMED充分混匀,随后快速加至胶板内(避免有气泡),插上梳子,室温静置至胶再次凝固,得到浓缩胶,最后,将凝固好的胶板用打湿厨房纸包好,放入含有少量蒸馏水的存胶盒中,4℃保存。
3.5凝胶电泳
将胶板卡至电源架上并放置于电泳槽内,加入10×电泳缓冲液至没过玻璃短板,缓慢拔出梳子,用移液器向最外两侧的上样孔中加入蛋白marker标志物,然后再依次向剩余孔中加入蛋白样品,蛋白样品上样质量为40μg,其中,电压设置条件为:80V电压持续30min跑浓缩胶,100V电压持续60min跑分离胶,待蓝色条带至分离胶底部或跑过目标蛋白后停止电泳。
3.6转膜
将PVDF膜放置于甲醇中活化1min后,和滤纸一起放入10×转膜液中,取出电泳结束的凝胶,按照滤纸、凝胶、活化好的PVDF膜、滤纸顺序依次叠放在电转夹上(在电转液中进行),夹好后依照正负极插入电转槽,其中,电转参数设置为200mA电流持续90min,注意整个叠放系统之间不能存在气泡,且需要对应好正负极。
3.7封闭和免疫印迹:
转膜结束后,用10×TBST溶液洗膜10min后,将PVDF膜置于5%BSA缓冲液中封闭1h,其中,用10×TBST溶液洗膜3次,每次10min,根据目标蛋白分子量裁剪好膜后放入配制好的一抗溶液(抗体:10×TBST溶液=1:1000)中,4℃孵育过夜,第二天用10×TBST溶液洗膜3次,每次10min,洗膜结束后,再放入配制好的二抗溶液(抗体:10×TBST溶液=1:2000)中,25℃敷育120min,随后用10×TBST溶液洗膜3次,每次10min,即可用于拍照保存。
3.8图像处理
获取蛋白表达图像后,使用ImageJ软件进行分析,得出对应的蛋白具体表达量数值,其图像和SYNJ1蛋白表达水平分别如图11和图12所示。
据图11和图12所示,与空白对照组大鼠相比,模型组大鼠前额叶皮质中的SYNJ1蛋白的相对表达显著增加(P<0.01),进一步验证空白对照组和模型组大鼠中的SYNJ1差异性表达。
5、空白对照组、模型组动物、给药组的PCR实验
参照“筛选基因差异性表达的PCR实验”的实验方法,对空白对照组、模型组动物、给药组大鼠前额叶皮质组织的SYNJ1 mRNA的相对表达量进行检测,检测结果如13图所示,
根据图13所示,模型组与空白对照组比较,SYNJ1mRNA的相对表达量显著增加,给药组与模型组相比较,SYNJ1 mRNA的相对表达量显著下降。
经以上分析可知,发明人采用PCR实验、蛋白免疫印迹实验的方法显示出抑郁症群体、非抑郁症群体以及经药物治疗后的抑郁症群体中表达具有显著差异的特定蛋白SYNJ1的标志物。此SYNJ1蛋白标志物将为抑郁症患者提供了一种新的标记物在辅助诊断的试剂盒的应用及其试剂盒,也为进一步阐明此类疾病的病理机制奠定基础。
尽管本发明的实施方案已公开如上,但其并不仅仅限于说明书和实施方式中所列运用,它完全可以被适用于各种适合本发明的领域,对于熟悉本领域的人员而言,可容易地实现另外的修改,因此在不背离权利要求及等同范围所限定的一般概念下,本发明并不限于特定的细节和这里示出与描述的图例。
Claims (3)
1.SYNJ1蛋白标记物在制备用于抑郁症辅助诊断的试剂盒中的应用。
2.如权利要求1所述的SYNJ1蛋白标记物在制备用于抑郁症辅助诊断的试剂盒中的应用,其特征在于,所述抑郁症包括内源性抑郁症、反应性抑郁症、隐匿性抑郁症、药物引起的继发性抑郁症、更年期抑郁症、产后抑郁症、脑外伤诱发的抑郁症、脑卒中诱发的抑郁症或抑郁性神经症。
3.如权利要求1所述的SYNJ1蛋白标记物制备得到的用于抑郁症辅助诊断的试剂盒。
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