CN112746104A - 血清中用于肝脏损伤疾病早期诊断的分子标记物 - Google Patents
血清中用于肝脏损伤疾病早期诊断的分子标记物 Download PDFInfo
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Abstract
本发明公开了血清中用于肝脏损伤疾病早期诊断的分子标记物。检测待检者血清中SIX1(sineoculis homeobox homolog 1)基因表达量的物质在制备如下任一产品中的应用，(a)检测或者辅助检测待检者是否患有肝病的产品；(b)诊断或者辅助诊断待检者是否患有肝病的产品。本发明收集了病毒性肝炎、脂肪肝、自身免疫性肝炎和遗传性肝病等各种肝病患者的血清和肝组织样本，用酶联免疫吸附实验(Enzyme‑linked immunosorbent assay，ELISA)方法和免疫病理染色等方法来检测血清和组织中SIX1，证明了SIX1可以作为一种新的肝脏损害与修复再生的临床生物指标，代表肝脏损伤与修复再生的标记物(MARKERS)。
Description
技术领域
本发明涉及生物医学技术领域，具体涉及一种血清中用于肝脏损伤疾病早期诊断的分子标记物。
背景技术
各种原因导致的肝病是目前影响我国人民健康的主要因素之一，包括病毒性肝炎、脂肪肝、自身免疫性肝炎、药物性肝炎和遗传性肝病等。近年来，随着生活水平的提高，人们的酒精和食物(糖)摄入量呈升高趋势，酒精性肝病/脂肪肝已成为不可忽视的公共健康问题。初期通常表现为脂肪肝，进而可发展成酒精性肝炎、肝纤维化和肝硬化。随着近年来各种先进医疗诊断技术的发展和疾病认识的提高，使得过去难于诊断的自身免疫性肝炎和遗传性肝病等临床上也不再罕见。各种病毒性肝炎、脂肪肝、自身免疫性肝炎和遗传性肝病等愈来愈成为严重影响人民健康的因素，这些肝病终末期可导致肝硬化或肝癌。虽然近年来针对这些肝病的发病机理和药物研究等有了巨大进步，病毒性肝炎的抗病毒治疗药物有了突破性的发展，但是对这些肝病的发生发展和再生修复的机制仍然尚不完全清楚，判断肝病病情发展的生物标志物严重缺乏，成为临床判断肝病严重程度的难题之一。目前临床常用的血清肝功能检测标志物或方法包括：肝功能检测：谷丙转氨酶(alanineaminotransferase,ALT)，谷草转氨酶(aspertate Aminotransferase,AST)，碱性磷酸酶(alkaline phosphatase,ALP)，谷氨酰转肽酶(glutamyl transpeptidase,GGT)，总蛋白(total protein,TP)，白蛋白(albumin,Alb)；球蛋白(glubulin,G)；A/G:白球蛋白比例(ALB/globulin ratio),总胆红素(total bilirubin,TBIL),间接胆红素(indirectbilirubin,IB)，直接胆红素(direct bilirubin,DBIL)，甲胎蛋白(alpha fetalprotein,AFP)，甘胆酸(cholyglycine,CG)，铁蛋白(serum ferritin,SF)，前白蛋白(prealbumin,PA)，转铁蛋白(transferrin,TF)，总胆汁酸(total bile acid,TBA)。肝纤六项：透明质酸(hyaluronic acid，HA)，层粘连蛋白(laminin，LN)，IV型胶原(collagen Type IV，IV-C)，Ⅲ型前胶原N端肽(type precollagenⅢN peptide，PⅢNP)，甘胆酸、纤维连接蛋白(fibronectin，FN)；高尔基体蛋白73(golgi protein73)，异常凝血酶原(protein inducedby vitamin K absence or antagonist-II，PIVKA-II)等。
目前，现有的检测指标的缺少/缺陷，不能很好的反应肝脏病理情况，亟待研发一种新的用于诊断肝脏疾病的检测物质。
发明内容
为此，本发明提供一种检测待检者血清中Six1基因表达量的物质的用途。
为了实现上述目的，本发明提供如下技术方案：
本发明提供了检测待检者血清中Six1基因表达量的物质在制备如下任一产品中的应用，
(a)检测或者辅助检测待检者是否患有肝病的产品；
(b)诊断或者辅助诊断待检者是否患有肝病的产品。
本发明的一个实施例中，所述肝病包括慢性乙型肝炎，肝纤维化、脂肪肝病、酒精性肝病、暴发性肝衰竭、药物性肝损、遗传性肝病、自身免疫性肝病或丙型肝炎。
本发明还提供了检测待检者血清中Six1基因表达量的物质在制备如下任一产品中的应用，(a)检测或者辅助检测待检者是否患有肝病的产品；
(b)诊断或者辅助诊断待检者是否患有肝病的产品。
所述待检者中，与健康人比较，若所述Six1基因表达，判定为肝病患者；若Six1基因不表达，判定为非肝病患者。
本发明的一个实施例中，所述检测待检者血清中Six1基因表达量的物质包括扩增Six1基因的引物对。
本发明的一个实施例中，所述检测待检者血清中Six1基因表达量的物质包括与SIX1蛋白特异性结合的抗体。
本发明还提供了一种产品，其包括检测待检者血清中Six1基因表达量的物质；
所述产品具有如下任一功能：(a)检测或者辅助检测待检者是否患有肝病；(b)诊断或者辅助诊断待检者是否患有肝病。
本发明的一个实施例中，所述肝病包括慢性乙型肝炎，肝纤维化、脂肪肝病、酒精性肝病、暴发性肝衰竭、药物性肝损、遗传性肝病、自身免疫性肝病或丙型肝炎。
本发明的一个实施例中，所述待检者中，与健康人比较，若所述Six1基因表达，判定为肝病患者；若Six1基因不表达，判定为非肝病患者。
本发明具有如下优点：
本发明收集了病毒性肝炎、脂肪肝、自身免疫性肝炎和遗传性肝病等各种肝病患者的血清和肝组织样本，用ELISA方法和免疫病理染色等方法来检测血清和组织中SIX1，证明了SIX1可以作为一种新的肝脏损害与修复再生的临床生物指标，代表肝脏损伤与修复再生的标记物(MARKERS)，为研制新的检测试剂盒提供一种新的方法和目标。有助于提升我国肝病的诊治水平，同时具有很好的经济效益。
附图说明
为了更清楚地说明本发明的实施方式或现有技术中的技术方案，下面将对实施方式或现有技术描述中所需要使用的附图作简单地介绍。显而易见地，下面描述中的附图仅仅是示例性的，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据提供的附图引伸获得其它的实施附图。
本说明书所绘示的结构、比例、大小等，均仅用以配合说明书所揭示的内容，以供熟悉此技术的人士了解与阅读，并非用以限定本发明可实施的限定条件，故不具技术上的实质意义，任何结构的修饰、比例关系的改变或大小的调整，在不影响本发明所能产生的功效及所能达成的目的下，均应仍落在本发明所揭示的技术内容得能涵盖的范围内。
图1为本发明实施例提供的慢性乙型肝炎患者SIX1,EYA1(Eyes absent 1)和人血清白蛋白(human serum albumin,HSA)的肝脏组织的免疫荧光染色图，其中，Panel A,Band C:CHB liver(慢乙肝肝组织)；Panel D and E:healthy control liver(健康肝组织对照)；
图2为本发明实施例提供的慢性乙型肝炎患者EYA1在转基因小鼠肝脏组织星状细胞中的表达的免疫荧光染色图；
图3为本发明实施例提供的慢性乙型肝炎患者SIX1在转基因小鼠肝脏星状细胞中的表达的免疫荧光染色图。
具体实施方式
以下由特定的具体实施例说明本发明的实施方式，熟悉此技术的人士可由本说明书所揭露的内容轻易地了解本发明的其他优点及功效，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1、ELISA方法检测肝病患者血清中的SIX1/EYA1蛋白
本实施例中，Six和Eya基因家族与动植物和人的多种器官的发育有关。哺乳动物基因组中有6个Six基因和4个Eya基因。Six基因编码和DNA直接结合的转录因子，EYA是一个转录的辅助因子，通过和它的下游靶点SIX形成复合体来影响转录，大量的研究已发现SIX1/EYA1与细胞的增殖，分化和维持有关，影响多种脏器的发育、疾病及肿瘤的发生。
Six1基因全序列如SEQ ID NO.1所示，蛋白质的氨基酸序列如2所示。该Six1基因全序列(NCBI Reference Sequence:NM_005982.4)。https://www.ncbi.nlm.nih.gov/nuccore/NM_005982.4。其中，SIX1基因的扩增引物序列如下所示：
Forward primer：AACAGGATTGGCTTGCTTGTG；
Reverse primer1：ATTTCTCCGTGGCCCAAGAC。
Eya1基因全序列(NCBI Reference Sequence:NM_001370333.1)https://www.ncbi.nlm.nih.gov/nuccore/NM_001370333.1。该Eix1基因的SEQ ID NO.3所示，蛋白质的氨基酸序列如4所示；Eya1基因的扩增引物序列如下所示：
Forward primer：TAAACACCGAGGCAGAACCC；
Reverse primer：GTGCCATTGGGAGTCATGGA。
从第三军医大学西南医院感染病科门诊和住院部收集的患者血清，住院患者中采集了313名慢性乙型肝炎(chronic hepatitis B，CHB)患者、153名其他肝病患者和33名健康对照者的血清，健康对照者的血清收集自健康管理中心，使用了ELISA方法对血清中的SIX1蛋白用ELISA方法进行了检测。对上述患者血清进行ELISA检测，包括以下试验步骤:
将含有包被抗体的96孔板放置在4℃过夜，第二天开始实验前去除上清液，每个适当的孔中加入适当稀释的标准品SIX1/EYA1蛋白或样品50μl，然后加入辣根过氧化物酶(Horseradish Peroxidase,HRP)标记的检测抗体100μl并在37℃，60分钟。
然后对96孔板进行4次清洗，然后分别加入底物50μl TMB显色液(3,3',5,5'-四甲基联苯胺)，在37℃放置15分钟，避光。
最后每个孔中加入50μl 1M盐酸终止液，在15分钟内用酶标仪(Multiskan，ThermoScientific，Waltham，MA，美国)测量每个孔在450nm的光密度(optical density，O.D)，然后根据标准曲线计算出每个样本的蛋白浓度，检测结果如表1至表3所示。
表1.慢乙肝患者和健康人血清中SIX1 and EYA1的水平
表2.其它肝病患者血清中SIX1 and EYA1的水平
表3.动态观察35个慢乙肝患者血清中SIX1和EYA1的变化
血清检测结果如表1至表3所示，结果显示313例慢性乙型肝炎患者血清SIX1和EYA1水平分别为7.24±0.11ng/ml和25.21±0.51ng/ml，显著高于33例健康对照者(2.84±0.15ng/ml和13.11±1.01ng/ml；P＜0.05)。肝纤维化、脂肪肝、酒精性肝病、暴发性肝衰竭、自身免疫性肝病和丙型肝炎患者血清SIX1也比健康对照组血清SIX1显著升高(P＜0.05)。动态观察35例慢性乙型肝炎患者中SIX1和EYA1血清水平在34至193天的间隔内增加，而丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)水平均低于100IU/L。
实施例2、SIX1、EYA1、人血清白蛋和胶质纤维酸性蛋白的免疫荧光检测
本实施中，人或者转基因小鼠肝脏组织切片中SIX1、EYA1、人血清白蛋白HSA和胶质纤维酸性蛋白(glial fibrillary acidic protein，GFAP)的免疫荧光染色包括以下步骤：
将慢性肝炎患者的人或者转基因小鼠肝脏组织冰冻切片用100％乙醇固定15分钟，用0.05％吐温20通透化细胞两次，每次处理2分钟。然后在常温下用3％牛血清白蛋白阻断30分钟。用PBS洗涤后，用兔抗人SIX1一级抗体(1:100稀释度)(HPA001893，Sigma，St.Louis，MO USA)或兔抗人EYA1一级抗体(1:100稀释度)(ab85009，abcam，Cambridge，MA，美国)和小鼠抗人HSA一级抗体(1:1000稀释度)(MAB1455，R&D Systems，Minneapolis MN，USA)或小鼠抗人GFAP一级抗体(1:100稀释度)(MA5-12023，ThermoFisher，Waltham，MA，USA)在4℃过夜。
然后将切片与Alexa
驴抗鼠IgG和Alexa
驴抗兔IgG(1:1000稀释度)(A21202，A10042，ThermoFisher，Waltham，MA，USA)在常温下孵育1小时。
用PBS洗涤后，用4'，6-二氨基-2-苯基吲哚(4’,6-diamidino-2-phenylindole,DAPI)对切片进行反染色。最后，用抗褪色介质贴上盖玻片，用奥林匹斯Olympus DP72显微镜和cellSens Standard 1.5软件观察并记录免疫荧光信号。
如图1至图3所示，慢性乙型肝炎患者肝脏组织免疫荧光染色显示SIX1和EYA1仅在肝星状细胞中表达，而且在慢性乙型肝炎组织中表达明显，但在正常肝组织中不明显。
本发明实施例在人Eya1LacZ转基因小鼠和Six1LacZ转基因小鼠上的研究发现Eya1和Six1基因主要在肝脏的卫星细胞中表达，Six1/Eya1基因与肝细胞的再生有关研究提示SIX1和EYA1都是慢性乙型肝炎和其他肝脏疾病肝损伤的新的生物标志物，具有潜在的临床应用价值。
虽然，上文中已经用一般性说明及具体实施例对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
序列表
<110> 丁建强
<120> 血清中用于肝脏损伤疾病早期诊断的分子标记物
<130> GG20872230A
<160> 4
<170> SIPOSequenceListing 1.0
<210> 1
<211> 855
<212> DNA
<213> Artificial Sequence
<400> 1
atgtcgatgc tgccgtcgtt tggctttacg caggagcaag tggcgtgcgt gtgcgaggtt 60
ctgcagcaag gcggaaacct ggagcgcctg ggcaggttcc tgtggtcact gcccgcctgc 120
gaccacctgc acaagaacga gagcgtactc aaggccaagg cggtggtcgc cttccaccgc 180
ggcaacttcc gtgagctcta caagatcctg gagagccacc agttctcgcc tcacaaccac 240
cccaaactgc agcaactgtg gctgaaggcg cattacgtgg aggccgagaa gctgcgcggc 300
cgacccctgg gcgccgtggg caaatatcgg gtgcgccgaa aatttccact gccgcgcacc 360
atctgggacg gcgaggagac cagctactgc ttcaaggaga agtcgagggg tgtcctgcgg 420
gagtggtacg cgcacaatcc ctacccatcg ccgcgtgaga agcgggagct ggccgaggcc 480
accggcctca ccaccaccca ggtcagcaac tggtttaaga accggaggca aagagaccgg 540
gccgcggagg ccaaggaaag ggagaacacc gaaaacaata actcctcctc caacaagcag 600
aaccaactct ctcctctgga agggggcaag ccgctcatgt ccagctcaga agaggaattc 660
tcacctcccc aaagtccaga ccagaactcg gtccttctgc tgcagggcaa tatgggccac 720
gccaggagct caaactattc tctcccgggc ttaacagcct cgcagcccag tcacggcctg 780
cagacccacc agcatcagct ccaagactct ctgctcggcc ccctcacctc cagtctggtg 840
gacttggggt cctaa 855
<210> 2
<211> 284
<212> PRT
<213> Artificial Sequence
<400> 2
Met Ser Met Leu Pro Ser Phe Gly Phe Thr Gln Glu Gln Val Ala Cys
1 5 10 15
Val Cys Glu Val Leu Gln Gln Gly Gly Asn Leu Glu Arg Leu Gly Arg
20 25 30
Phe Leu Trp Ser Leu Pro Ala Cys Asp His Leu His Lys Asn Glu Ser
35 40 45
Val Leu Lys Ala Lys Ala Val Val Ala Phe His Arg Gly Asn Phe Arg
50 55 60
Glu Leu Tyr Lys Ile Leu Glu Ser His Gln Phe Ser Pro His Asn His
65 70 75 80
Pro Lys Leu Gln Gln Leu Trp Leu Lys Ala His Tyr Val Glu Ala Glu
85 90 95
Lys Leu Arg Gly Arg Pro Leu Gly Ala Val Gly Lys Tyr Arg Val Arg
100 105 110
Arg Lys Phe Pro Leu Pro Arg Thr Ile Trp Asp Gly Glu Glu Thr Ser
115 120 125
Tyr Cys Phe Lys Glu Lys Ser Arg Gly Val Leu Arg Glu Trp Tyr Ala
130 135 140
His Asn Pro Tyr Pro Ser Pro Arg Glu Lys Arg Glu Leu Ala Glu Ala
145 150 155 160
Thr Gly Leu Thr Thr Thr Gln Val Ser Asn Trp Phe Lys Asn Arg Arg
165 170 175
Gln Arg Asp Arg Ala Ala Glu Ala Lys Glu Arg Glu Asn Thr Glu Asn
180 185 190
Asn Asn Ser Ser Ser Asn Lys Gln Asn Gln Leu Ser Pro Leu Glu Gly
195 200 205
Gly Lys Pro Leu Met Ser Ser Ser Glu Glu Glu Phe Ser Pro Pro Gln
210 215 220
Ser Pro Asp Gln Asn Ser Val Leu Leu Leu Gln Gly Asn Met Gly His
225 230 235 240
Ala Arg Ser Ser Asn Tyr Ser Leu Pro Gly Leu Thr Ala Ser Gln Pro
245 250 255
Ser His Gly Leu Gln Thr His Gln His Gln Leu Gln Asp Ser Leu Leu
260 265 270
Gly Pro Leu Thr Ser Ser Leu Val Asp Leu Gly Ser
275 280
<210> 3
<211> 1866
<212> DNA
<213> Artificial Sequence
<400> 3
atggaagacc cccgggggat aaatggacag tctgtgcaaa catctcaagc cagttcagat 60
gttgctgttt cctcaagttg caggtctatg gaaatgcagg atctaaccag cccgcatagc 120
cgtctgagtg gtagtagtga atcccccagt ggccccaaac tcggtaactc tcatataaat 180
agtaattcca tgactcccaa tggcaccgaa gttaaaacag agccaatgag cagcagtgaa 240
acagcttcaa cgacagccga cgggtcttta aacaatttct caggttcagc aattgggagc 300
agtagtttca gcccacgacc aactcaccag ttctctccac cacagattta cccttccaac 360
agaccatacc cacatattct ccctacccct tcctcacaaa ctatggctgc atatgggcaa 420
acacagttta ccacaggaat gcaacaagct acagcctatg ccacgtaccc acagccagga 480
cagccgtacg gcatttcctc atatggtgca ttgtgggcag gcatcaagac tgaaggtgga 540
ttgtcacagt ctcagtcacc tggacagaca ggatttctca gctatggcac aagcttcagt 600
acccctcaac ctggacaggc accatacagc taccagatgc aaggtagcag ttttacaaca 660
tcatcaggaa tatatacagg aaataattca ctcacaaatt cctctggatt taatagttca 720
cagcaggact atccgtctta tcccagtttt ggccagggtc agtacgcaca gtattataac 780
agctcaccgt atccagcaca ttatatgacc agcagcaaca ccagcccaac gacaccatcc 840
accaatgcca cttaccagct tcaagaaccg ccatctggca tcaccagcca agcagttaca 900
gatcccacag cagagtacag cacaatccac agcccatcaa cacccattaa agattcagat 960
tctgatcgat tgcgtcgagg ttcagatggg aaatcacgtg gacggggccg aagaaacaat 1020
aatccttcac ctcccccaga ttctgatctt gagagagtgt tcatctggga cttggatgag 1080
acaatcattg ttttccactc cttgcttact gggtcctacg ccaacagata tgggagggat 1140
ccacccactt cagtttccct tggactgcga atggaagaaa tgattttcaa cttggcagac 1200
acacatttat tttttaatga cttagaagaa tgtgaccaag tccatataga tgatgtttct 1260
tcagatgata acggacagga cctaagcaca tataactttg gaacagatgg ctttcctgct 1320
gcagcaacca gtgctaactt atgtttggca actggtgtac ggggcggtgt ggactggatg 1380
agaaagttgg ccttccgcta cagacgggta aaagagatct acaacaccta caaaaataat 1440
gttggaggtc tgcttggtcc agctaagagg gaagcctggc tgcagttgag ggccgaaatt 1500
gaagccctga ccgactcctg gttgacactg gccctgaaag cactctcgct cattcactcc 1560
cggacaaact gtgtgaatat tttagtaaca actactcagc tcatcccagc attggcgaaa 1620
gtcctgctgt atgggttagg aattgtattt ccaatagaaa atatttacag tgcaactaaa 1680
ataggaaaag aaagctgttt tgagagaata attcaaaggt ttggaagaaa agtggtgtat 1740
gttgttatag gagatggtgt agaagaagaa caaggagcaa aaaagcacgc gatgcccttc 1800
tggaggatct ccagccactc ggacctcatg gccctgcacc atgccttgga actggagtac 1860
ctgtaa 1866
<210> 4
<211> 621
<212> PRT
<213> Artificial Sequence
<400> 4
Met Glu Asp Pro Arg Gly Ile Asn Gly Gln Ser Val Gln Thr Ser Gln
1 5 10 15
Ala Ser Ser Asp Val Ala Val Ser Ser Ser Cys Arg Ser Met Glu Met
20 25 30
Gln Asp Leu Thr Ser Pro His Ser Arg Leu Ser Gly Ser Ser Glu Ser
35 40 45
Pro Ser Gly Pro Lys Leu Gly Asn Ser His Ile Asn Ser Asn Ser Met
50 55 60
Thr Pro Asn Gly Thr Glu Val Lys Thr Glu Pro Met Ser Ser Ser Glu
65 70 75 80
Thr Ala Ser Thr Thr Ala Asp Gly Ser Leu Asn Asn Phe Ser Gly Ser
85 90 95
Ala Ile Gly Ser Ser Ser Phe Ser Pro Arg Pro Thr His Gln Phe Ser
100 105 110
Pro Pro Gln Ile Tyr Pro Ser Asn Arg Pro Tyr Pro His Ile Leu Pro
115 120 125
Thr Pro Ser Ser Gln Thr Met Ala Ala Tyr Gly Gln Thr Gln Phe Thr
130 135 140
Thr Gly Met Gln Gln Ala Thr Ala Tyr Ala Thr Tyr Pro Gln Pro Gly
145 150 155 160
Gln Pro Tyr Gly Ile Ser Ser Tyr Gly Ala Leu Trp Ala Gly Ile Lys
165 170 175
Thr Glu Gly Gly Leu Ser Gln Ser Gln Ser Pro Gly Gln Thr Gly Phe
180 185 190
Leu Ser Tyr Gly Thr Ser Phe Ser Thr Pro Gln Pro Gly Gln Ala Pro
195 200 205
Tyr Ser Tyr Gln Met Gln Gly Ser Ser Phe Thr Thr Ser Ser Gly Ile
210 215 220
Tyr Thr Gly Asn Asn Ser Leu Thr Asn Ser Ser Gly Phe Asn Ser Ser
225 230 235 240
Gln Gln Asp Tyr Pro Ser Tyr Pro Ser Phe Gly Gln Gly Gln Tyr Ala
245 250 255
Gln Tyr Tyr Asn Ser Ser Pro Tyr Pro Ala His Tyr Met Thr Ser Ser
260 265 270
Asn Thr Ser Pro Thr Thr Pro Ser Thr Asn Ala Thr Tyr Gln Leu Gln
275 280 285
Glu Pro Pro Ser Gly Ile Thr Ser Gln Ala Val Thr Asp Pro Thr Ala
290 295 300
Glu Tyr Ser Thr Ile His Ser Pro Ser Thr Pro Ile Lys Asp Ser Asp
305 310 315 320
Ser Asp Arg Leu Arg Arg Gly Ser Asp Gly Lys Ser Arg Gly Arg Gly
325 330 335
Arg Arg Asn Asn Asn Pro Ser Pro Pro Pro Asp Ser Asp Leu Glu Arg
340 345 350
Val Phe Ile Trp Asp Leu Asp Glu Thr Ile Ile Val Phe His Ser Leu
355 360 365
Leu Thr Gly Ser Tyr Ala Asn Arg Tyr Gly Arg Asp Pro Pro Thr Ser
370 375 380
Val Ser Leu Gly Leu Arg Met Glu Glu Met Ile Phe Asn Leu Ala Asp
385 390 395 400
Thr His Leu Phe Phe Asn Asp Leu Glu Glu Cys Asp Gln Val His Ile
405 410 415
Asp Asp Val Ser Ser Asp Asp Asn Gly Gln Asp Leu Ser Thr Tyr Asn
420 425 430
Phe Gly Thr Asp Gly Phe Pro Ala Ala Ala Thr Ser Ala Asn Leu Cys
435 440 445
Leu Ala Thr Gly Val Arg Gly Gly Val Asp Trp Met Arg Lys Leu Ala
450 455 460
Phe Arg Tyr Arg Arg Val Lys Glu Ile Tyr Asn Thr Tyr Lys Asn Asn
465 470 475 480
Val Gly Gly Leu Leu Gly Pro Ala Lys Arg Glu Ala Trp Leu Gln Leu
485 490 495
Arg Ala Glu Ile Glu Ala Leu Thr Asp Ser Trp Leu Thr Leu Ala Leu
500 505 510
Lys Ala Leu Ser Leu Ile His Ser Arg Thr Asn Cys Val Asn Ile Leu
515 520 525
Val Thr Thr Thr Gln Leu Ile Pro Ala Leu Ala Lys Val Leu Leu Tyr
530 535 540
Gly Leu Gly Ile Val Phe Pro Ile Glu Asn Ile Tyr Ser Ala Thr Lys
545 550 555 560
Ile Gly Lys Glu Ser Cys Phe Glu Arg Ile Ile Gln Arg Phe Gly Arg
565 570 575
Lys Val Val Tyr Val Val Ile Gly Asp Gly Val Glu Glu Glu Gln Gly
580 585 590
Ala Lys Lys His Ala Met Pro Phe Trp Arg Ile Ser Ser His Ser Asp
595 600 605
Leu Met Ala Leu His His Ala Leu Glu Leu Glu Tyr Leu
610 615 620
Claims (8)
1.检测待检者血清中Six1基因表达量的物质在制备如下任一产品中的应用，
(a)检测或者辅助检测待检者是否患有肝病的产品；
(b)诊断或者辅助诊断待检者是否患有肝病的产品。
2.如权利要求1所述的应用，其特征在于，
所述肝病包括慢性乙型肝炎，肝纤维化、脂肪肝病、酒精性肝病、暴发性肝衰竭、药物性肝损、遗传性肝病、自身免疫性肝病或丙型肝炎。
3.检测待检者血清中Six1基因表达量的物质在制备如下任一产品中的应用，
(a)检测或者辅助检测待检者是否患有肝病的产品；
(b)诊断或者辅助诊断待检者是否患有肝病的产品，
所述待检者中，与健康人比较，若所述Six1基因表达过量，判定为肝病患者；若Six1基因不表达不过量，判定为非肝病患者。
4.如权利要求1-3中任一所述的应用，其特征在于，
所述检测待检者血清中Six1基因表达量的物质包括扩增Six1基因的引物对。
5.如权利要求1-3中任一所述的应用，其特征在于，
所述检测待检者血清中Six1基因表达量的物质包括与SIX1蛋白特异性结合的抗体。
6.一种产品，其特征在于，包括检测待检者血清中Six1基因表达量的物质；
所述产品具有如下任一功能：(a)检测或者辅助检测待检者是否患有肝病；(b)诊断或者辅助诊断待检者是否患有肝病。
7.如权利要求6所述的产品，其特征在于，
所述肝病包括慢性乙型肝炎，肝纤维化、脂肪肝病、酒精性肝病、暴发性肝衰竭、药物性肝损、遗传性肝病、自身免疫性肝病或丙型肝炎。
8.如权利要求6所述的产品，其特征在于，
所述待检者中，与健康人比较，若所述Six1基因表达，判定为肝病患者；若Six1基因不表达，判定为非肝病患者。
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Application publication date: 20210504 |