CN108280323A - 影响尿路结石形成的标靶基因和关键信号通路及其用途 - Google Patents
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Abstract
本发明公开十个影响尿路结石形成的标靶基因/蛋白(DMBT1、CAV1、CAV2、ZNF408、LRP2、HSPG2、CALML5、CDH3、DAPK3和LAMC1)和一个影响尿路结石形成的关键信号通路,粘着斑信号通路(Focal adhesion pathway),可用于尿路结石形成的早期预测和作为靶点开发尿路结石防治药物。
Description
技术领域
本发明涉及识别尿路结石形成的标靶基因和关键信号通路。
背景技术
尿路结石疾病是一种由环境饮食因素和遗传因素引起的复杂疾病,绝大部分起源于肾脏,以肾小管或肾间质的结晶异常沉积为特征,临床常表现为肾脏功能损害和尿路梗阻,发病率超过6-12%,五年再发率达50%,并可终生多次再发。由于尿路结石的形成机制复杂,至今对其分子形成机制仍不清楚,导致目前临床缺乏有效的治疗和预防措施,而多以碎石、手术等方式暂时缓解症状,不能在肾脏钙化的发病机制上对结石形成进行有效的药物抑制和再发预防。
肾结石形成是肾脏及其内外环境与基因之间复杂的相互作用的过程。肾脏在保持和调节人体水、盐平衡,排除代谢废物的同时,易在肾小管形成盐的过饱和状态,在常见的代谢异常如高草酸尿、高钙尿的风险环境下,结晶沉积在肾小管或肾间质,导致肾脏钙化,结晶不断成核,聚集和生长,最终形成肾结石。在这个过程中,肾脏通过主动或被动的生物学行为表达和分泌一些大分子蛋白参与和影响结石形成。最近,有研究者通过蛋白质组学、基因组范围的相关性研究和Microarray技术发现了数以万计的基因或蛋白可能与肾结石形成相关,如何处理这些数据从中获得影响肾结石形成的标靶基因和关键信号通路是一个巨大的挑战。
蛋白质-蛋白质相互作用(PPI)决定着从转录调节到酶级连反应的几乎所有的生物功能,这方面的研究具有重要的科学价值和应用前景。新近发展出了很多在基因组水平上和蛋白水平上用理论方法和已知的蛋白互作网络数据库分析某蛋白的PPI及其相互作用网络的技术,对功能基因组研究具有十分重要的意义,有助于蛋白质功能的分析、疾病致病机理的阐明和治疗新药的开发等众多难题的解决,是目前生命科学的前沿领域之一。
目前市场上由于不清楚作用靶点,对于尿路结石的治疗药物还很缺乏,现有的药物多以扩张输尿管和增加尿量为主,而还很少有能在肾结石形成机制基础上抑制结石的药物。获得尿路结石形成的marker基因/蛋白和关键信号通路将为开发尿路结石抑制药物提供重要靶点。
发明内容
本发明要解决的问题是通过基因/蛋白质相互作用网络分析方法识别影响尿路结石形成的marker基因/蛋白和关键信号通路,从而为研发尿路结石治疗药物提供靶点。
为了解决上述问题,本发明通过如下技术方案实现:
从尿路结石基因组相关数据,获得258个相关一碱基多型变异(P<10-4),将这些变异定位到基因,得到275个候选基因。
从尿路结石微阵列数据,获得2倍表达差异的2156个上调基因和267个下调基因。
从尿路结石蛋白质组学数据,获得814个差异表达的尿蛋白。
将上述[0008]尿路结石基因组的275个候选基因整合进人类蛋白质相互作用网络(Biogrid),得到一个含有1781基因的直接网络(如图2)。
将上述[0009]尿路结石微阵列差异表达基因(包括上调和下调基因)整合进人类蛋白质相互作用网络(Biogrid),得到一个含有38基因的直接网络(如图2)。
将上述[0010]尿路结石蛋白质组814差异表达的尿蛋白整合进人类蛋白质相互作用网络(Biogrid),得到一个含有194蛋白的结石患者直接网络(如图3A)和含有235蛋白的非结石患者的尿蛋白相互作用直接网络(如图3B)。
上述[0011][0012][0013]经Permutation test计算,P<0.05,显示这些网络比随机构建的网络具有显著更多的相互作用连接,它们的改变将在不同层面(基因变异、基因表达、蛋白水平)影响尿路结 石的形成。
Overlap分析显示,DMBT1、CAV1、CAV2、ZNF408、LRP2、HSPG2基因共同存在于基因变异和基因表达改变层面;CALML5、DAPK3和LAMC1共同存在于基因表达和尿蛋白差异表达层面,CDH3存在于基因变异和尿蛋白差异表达层面。这些不同层面的改变累积在这些基因或蛋白将增加尿路结石形成风险和促进结石形成,这些基因/蛋白可以作为marker,通过基因检测、表达分析和尿液分析方法进行检测(如图4)。
对上述[0011][0012][0013]直接网络中的基因或蛋白进行信号通路聚类分析发现,这三个层面富集的信号通路汇聚在共同的两个信号通路,即Focal adhesion和Proteoglycans in cancer信号通路。
本发明中,两个关键信号通路(Focal adhesion和Proteoglycans in cancer)可作为开发尿路结石药物提供了药物靶点。Focal adhesion信号通路包括193个基因(如下表)。
Focal adhesion信号通路包括193个基因
附图说明
图1.尿路结石相关变异基因的相互作用直接网络。
图2.尿路结石微阵列差异表达基因的相互作用直接网络。
图3.尿路结石蛋白质组差异表达的尿蛋白相互作用直接网络。
A.尿路结石患者的尿蛋白相互作用直接网络。B.非结石患者的尿蛋白相互作用直接网络。
图4.Overlap分析基因变异、基因表达、蛋白水平三个层面。
具体实施方式
本发明通过生物信息学技术对尿路结石形成进行蛋白相互作用网络研究,首次公开了十个影响尿路结石形成的关键基因/蛋白(DMBT1、CAV1、CAV2、ZNF408、LRP2、HSPG2、CALML5、CDH3、DAPK3和LAMC1)和两个关键信号通路(Focal adhesion和Proteoglycans incancer),为尿路结石形成预测提供了生物标记物和为开发尿路结石抑制药物提供了药物靶点。
DMBT1全称deleted in malignant brain tumors 1(Gene ID:1755),基因定位在10q26.13,也称SAG;GP340;SALSA;muclin。
CAV1全称caveolin 1(Gene ID:857),基因定位在7q31.1,也称CGL3;PPH3;BSCL3;LCCNS;VIP21;MSTP085,编码两种异构体,该蛋白与CAV2共同形成一个稳定的低聚复合体,是细胞膜小窝的主要成分。
CAV2全称caveolin 2(Gene ID:858),基因定位在7q31.2,也称CAV,编码两种异构体,该蛋白与CAV1共同形成一个稳定的低聚复合体,是细胞膜小窝的主要成分。
ZNF408,全称zinc finger protein 408(Gene ID:79797),基因定位在11p11.2,也称EVR6;RP72。
LRP2,全称LDL receptor related protein 2(Gene ID:4036),基因定位在2q31.1,也称DBS;GP330,是一个多配体内吞受体。
HSPG2,全称heparan sulfate proteoglycan 2(Gene ID:3339),基因定位在1p36.12,也称PLC;SJA;SJS;HSPG;SJS1;PRCAN。
CALML5,全称calmodulin like 5(Gene ID:51806),基因定位在10p15.1,也称CLSP。
CDH3,全称cadherin 3(Gene ID:1001),基因定位在16q22.1,也称CDHP;HJMD;PCAD。
DAPK3,全称death associated protein kinase 3(Gene ID:1613),基因定位在19p13.3,也称DLK;ZIP;ZIPK。
LAMC1全称laminin subunit gamma 1(Gene ID:3915),基因定位在1q25.3,也称LAMB2,是细胞外基质糖蛋白,也是细胞基底膜中主要的非胶原成分。
本发明中,术语“基因/蛋白”,指基因或蛋白,蛋白指基因编码的蛋白,可互换使用。
本发明中,“药物靶点”指基因上的变异位点或位点组合和蛋白序列的部分或全部。
本发明中,药物组合抑制剂包括:DMBT1的抗体、抑制性LnRNA、siRNA、shRNA以及DMBT1的活性抑制剂或促进剂;CAV1的抗体、抑制性LnRNA、siRNA、shRNA以及CAV1的活性抑制剂或促进剂;CAV2的抗体、抑制性LnRNA、siRNA、shRNA以及CAV2的活性抑制剂或促进剂;ZNF408的抗体、抑制性LnRNA、siRNA、shRNA以及ZNF408的活性抑制剂或促进剂;LRP2的抗体、抑制性LnRNA、siRNA、shRNA以及LRP2的活性抑制剂;HSPG2的抗体、抑制性LnRNA、siRNA、shRNA以及HSPG2的活性抑制剂;CALML5的抗体、抑制性LnRNA、siRNA、shRNA以及CALML5的活性抑制剂;CDH3的抗体、抑制性LnRNA、siRNA、shRNA以及CDH3的活性抑制剂;DAPK3的抗体、抑制性LnRNA、siRNA、shRNA以及DAPK3的活性抑制剂;LAMC1的抗体、抑制性LnRNA、siRNA、shRNA以及LAMC1的活性抑制剂;Focal adhesion信号通路193基因的抗体、抑制性LnRNA、siRNA、shRNA及其活性抑制剂或促进剂。
Claims (8)
1.影响尿路结石形成的关键蛋白,其特征在于包含DMBT1、CAV1、CAV2、ZNF408、LRP2、HSPG2、CALML5、CDH3、DAPK3和LAMC1十种标靶基因或蛋白及它们的组合。
2.影响尿路结石形成的关键信号通路,其特征在于包含粘着斑信号通路(Focaladhesion)。
3.如权利要求1和2所述的DMBT1、CAV1、CAV2、ZNF408、LRP2、HSPG2、CALML5、CDH3、DAPK3和LAMC1十种标靶基因或蛋白、Focal adhesion关键信号通路包含的基因或蛋白来源于啮齿动物或人,更佳地,来源于人。
4.如权利要求1所述的DMBT1、CAV1、CAV2、ZNF408、LRP2、HSPG2、CALML5、CDH3、DAPK3和LAMC1十种关键基因或蛋白,其特征在于,可作为尿路结石形成预测的生物标记物和作为药物靶点的药物组合物。
5.如权利要求2所述的Focal adhesion关键信号通路,其特征在于,可作为抑制尿路结石形成的药物靶向信号通路。
6.如权利要求4和5所述的用途,其特征在于,所述的药物组合物包括抑制剂作为活性成分,以及药学上可接受的载体。
7.如权利要求4和5所述的用途,其特征在于,所述“药物靶点”包括DMBT1、CAV1、CAV2、ZNF408、LRP2、HSPG2、CALML5、CDH3、DAPK3和LAMC1十种基因/蛋白与Focal adhesion信号通路上的基因变异位点或蛋白的部分或全部。
8.如权利要求4和5所述的用途,其特征在于,所述的尿路结石形成预测包括对DMBT1、CAV1、CAV2、ZNF408、LRP2、HSPG2、CALML5、CDH3、DAPK3和LAMC1与Focal adhesion信号通路包含基因或基因组合的突变检测和蛋白表达量检测预测尿路结石形成。
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