WO2020140425A1 - 一组血清差异蛋白组合在制备用于检测孤独症的试剂中的应用 - Google Patents

一组血清差异蛋白组合在制备用于检测孤独症的试剂中的应用 Download PDF

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WO2020140425A1
WO2020140425A1 PCT/CN2019/097629 CN2019097629W WO2020140425A1 WO 2020140425 A1 WO2020140425 A1 WO 2020140425A1 CN 2019097629 W CN2019097629 W CN 2019097629W WO 2020140425 A1 WO2020140425 A1 WO 2020140425A1
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protein
serum
autism
serum differential
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姚芳
沈立明
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Shenzhen University
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    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

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  • the invention relates to the technical field of reagent application, in particular to the application of a group of serum differential protein combinations in the preparation of reagents for detecting autism.
  • Autism also known as autism, is a complex developmental disorder of the nervous system. The incidence rate is increasing year by year, bringing a heavy burden to families and society. Although genetics and the environment are recognized as the main factors of disease, the exact pathological mechanism is not yet clear. At present, there are no specific treatment drugs and specific diagnostic markers for autism, but early detection and early intervention can significantly improve patients' social communication and reduce their anxiety and aggressive behavior.
  • the current diagnosis of autism is mainly based on the neuropsychological test scale, clinical symptoms, patient or family description, and clinical experience of clinicians. It has a certain subjectivity and is prone to delay or misdiagnosis. Therefore, the search for rapid and effective detection reagents is of great significance for the early detection and intervention of diseases.
  • the purpose of the present invention is to provide a group of serum differential protein combinations in the preparation of reagents for the detection of autism, aiming to solve the existing detection method has a certain subjectivity and is prone to cause detection delay Or misdiagnosed problems.
  • serum differential protein combinations are any 3 or 3 of RARS protein, ACTL6B protein, PRKAA1 protein, SLC25A12 protein and LIMK1 protein Combination of the above proteins.
  • the high-throughput proteomics method is used to determine whether the serum differential protein combination exists in the serum.
  • determining that there is a serum differential protein combination in the serum further includes: using an enzyme-linked immunoassay technique to individually detect each protein in the serum differential protein combination to determine the concentration change of the detected serum differential protein.
  • determining the presence of the serum differential protein combination in the serum further includes: simultaneously detecting the serum differential protein using protein chip technology to determine the concentration change of the detected serum differential protein.
  • the present invention determines a serum differential protein combination that can be used to detect autism.
  • the combination of the serum differential protein for the preparation of reagents for detecting autism can improve the objectivity, specificity and accuracy of the detection.
  • Figure 1 is a comparison chart of ELISA results of RARS protein in the control group and the disease group.
  • Figure 2 is a comparison chart of ELISA test results of ACTL6B protein in the control group and the disease group.
  • Figure 3 is a comparison chart of ELISA test results of PRKAA1 protein in the control group and the disease group.
  • Figure 4 is a comparison chart of ELISA test results of SLC25A12 protein in the control group and the disease group.
  • Figure 5 is a comparison chart of ELISA test results of LIMK1 protein in the control group and the disease group.
  • Fig. 6 is a comparison chart of ELISA test results of POLR3C protein in the control group and the disease group.
  • Figure 7 is a comparison chart of ELISA test results of ARHGEF4 protein in the control group and the disease group.
  • Figure 8 is the receiver operating characteristic curve of RARS protein, ACTL6B protein, PRKAA1 protein, SLC25A12 protein and LIMK1 protein.
  • the present invention provides the application of a group of serum differential protein combinations in the preparation of reagents for detecting autism.
  • a group of serum differential protein combinations in the preparation of reagents for detecting autism.
  • the invention provides the application of a group of serum differential protein combinations in the preparation of reagents for detecting autism, wherein the serum differential protein combinations are any 3 of RARS protein, ACTL6B protein, PRKAA1 protein, SLC25A12 protein and LIMK1 protein Or a combination of more than 3 proteins.
  • the present invention provides the above-mentioned combination of serum differential proteins for preparing reagents for detecting autism.
  • the application of the reagent can improve the specificity and accuracy of disease detection, and at the same time has certain objectivity, which is better than a single disease marker.
  • Any three or more protein combinations in the serum differential proteins (a total of five) provided by the present invention can be used as autism detection markers. When these markers are used to detect autism, they have certain objectivity, specificity and accuracy.
  • the source of the autism detection marker of the present invention may be plasma, in addition to serum.
  • the above-mentioned serum differential protein combination of the present invention is a combination of SLC25A12 protein, LIMK1 protein and RARS protein.
  • the combined protein has better objectivity, specificity and accuracy when used as a marker for autism detection.
  • the above-mentioned serum differential protein combination of the present invention is a combination of SLC25A12 protein, LIMK1 protein and ACTL6B protein.
  • the combined protein also has better objectivity, specificity and accuracy when used as a marker for autism detection.
  • the above-mentioned serum differential protein combination of the present invention is a combination of PRKAA1 protein, SLC25A12 protein and LIMK1 protein.
  • the combined protein also has better objectivity, specificity and accuracy when used as a marker for autism detection.
  • the aforementioned serum differential protein combination is a combination of RARS protein, ACTL6B protein, LIMK1 protein and SLC25A12 protein.
  • the combined protein also has certain objectivity, specificity and accuracy when used as a marker for autism detection.
  • the aforementioned serum differential protein of the present invention is a combination of RARS protein, PRKAA1 protein, SLC25A12 protein and LIMK1 protein.
  • the combined protein also has certain objectivity, specificity and accuracy when used as a marker for autism detection.
  • the aforementioned serum differential protein of the present invention is a combination of RARS protein, ACTL6B protein, PRKAA1 protein, SLC25A12 protein and LIMK1 protein.
  • the combined protein also has certain objectivity, specificity and accuracy when used as a marker for autism detection.
  • the invention provides the application of a group of serum differential protein combinations in the preparation of reagents for detecting autism.
  • the patient's serum is collected, and the high-throughput proteomics method is used to determine whether the serum differential protein combination as described above exists in the serum.
  • the method for determining the presence of serum differential proteins in the serum further includes: using enzyme-linked immunoassay to detect the serum differential proteins one by one to determine the concentration change of the detected serum differential proteins.
  • the present invention can further improve the specificity, sensitivity and accuracy of the detection according to the detected change in the concentration of the serum differential protein.
  • the method for determining the presence of differential proteins in serum of the present invention further includes: using protein chip technology to simultaneously detect the differential proteins in serum to determine the concentration change of the detected differential proteins in serum.
  • the present invention can further improve the specificity, sensitivity and accuracy of the detection according to the detected concentration change of the serum differential protein.
  • the present invention uses a combination of computational prediction and experimental verification to identify blood protein markers that can be used in the diagnosis of autism: First, by comparing and analyzing the transcriptome data of brain tissues of existing autism patients and normal people, loneliness is obtained Differentially expressed genes related to autism; secondly, the protein encoded by the autism-related gene is secreted into the blood using the blood protein prediction program to obtain autism-related blood proteins; then, functional analysis is performed through autism-related blood proteins to select Potential blood protein markers of autism; Finally, blood samples of autistic patients and normal people were collected, and these proteins were experimentally verified by enzyme-linked immunoassay (ELISA). Therefore, the technical solution of the present invention has higher sensitivity and better specificity than the traditional method of proteomics in searching for blood protein markers of autism, which complies with the principle of "more, faster, better and less expensive".
  • the present invention identifies 364 autism-related differentially expressed genes by comparing and analyzing transcriptome data of brain tissues of 79 autism patients and normal humans.
  • the proteins encoded by 59 genes are predicted to be secreted into the blood and become blood proteins related to autism.
  • 7 proteins were selected as potential autism blood protein markers, and blood samples of patients and normal persons were collected and verified by ELISA experiments. The experimental results are shown in Figure 1 - Figure 7.
  • the calculated predictions of the seven proteins are compared with the experimentally verified results in Table 1.
  • LIMK1 can Stimulates axon growth and plays a role in neural development and synaptic plasticity, which is related to the occurrence of autism
  • RARS is an enzyme essential for RNA translation and plays an important role in myelination
  • ACTL6B It is a candidate risk gene for autism, with neuron-specific chromatin remodeling and neurodevelopmental functions
  • PRKAA1 is a catalytic subunit of protein kinase A and plays a key role in regulating cellular energy metabolism. The degradation of autism and protein kinases A-mediated reduction of protein phosphorylation level is related to abnormal cell signal.
  • the present invention adopts a new research strategy that combines computational prediction and experimental verification to perform mapping analysis from transcriptome data of brain tissue of autism patients to blood proteome data, and combined with ELISA experiments to screen out the ability to distinguish loneliness
  • the serum differential protein group is RARS protein, ACTL6B protein, PRKAA1 protein, SLC25A12 protein and LIMK1 protein. Any three or more protein combinations of this group of differential proteins can be used to prepare Reagents for detecting autism, combined with markers, can improve the accuracy and specificity of autism detection.

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Abstract

一组血清差异蛋白组合在制备用于检测孤独症的试剂中的应用，该血清差异蛋白组合为RARS蛋白、ACTL6B蛋白、PRKAA1蛋白、SLC25A12蛋白和LIMK1蛋白中的任意3种或3种以上蛋白的组合。将该血清差异蛋白组合用于制备检测孤独症的试剂，可提高检测的客观性、特异性和准确性。

Description

一组血清差异蛋白组合在制备用于检测孤独症的试剂中的应用 技术领域
本发明涉及试剂应用技术领域，尤其涉及一组血清差异蛋白组合在制备用于检测孤独症的试剂中的应用。
背景技术
孤独症又称自闭症，是一种复杂的神经系统发育障碍性疾病。其发病率逐年增高，给家庭和社会带来沉重的负担。尽管，遗传和环境被公认为是致病的主要因素，但其确切的病理机制尚未明确。目前，孤独症无特效治疗药物和特异性诊断标志物，但早发现、早干预可明显改善患者的社交沟通，并减少其焦虑和攻击行为。当前孤独症的诊断主要依据神经心理学测试量表、临床症状、患者或家属描述、临床医生的临床经验等，具有一定的主观性，易造成诊断延迟或误诊。因此，寻找快速、有效的检测试剂，对于疾病的早期检测和干预具有重大的意义。
因此，现有技术还有待于改进和发展。
发明内容
鉴于上述现有技术的不足，本发明的目的在于提供一组血清差异蛋白组合在制备用于检测孤独症的试剂中的应用，旨在解决现有检测方法具有一定的主观性，易造成检测延迟或误诊的问题。
本发明的技术方案如下：
一组血清差异蛋白组合在制备用于检测孤独症的试剂中的应用，其中，所述血清差异蛋白组合为RARS蛋白、ACTL6B蛋白、PRKAA1蛋白、SLC25A12蛋白和LIMK1蛋白中的任意3种或3种以上蛋白的组合。
所述的应用，其中，采集血清，通过高通量蛋白质组学方法确定血清中是否存在所述的血清差异蛋白组合。
所述的应用，其中，确定血清中存在血清差异蛋白组合还包括：采用酶联免疫技术对血清差异蛋白组合中的各个蛋白进行逐个检测，确定检测到的血清差异蛋白的浓度变化。
所述的应用，其中，确定血清中存在血清差异蛋白组合还包括：采用蛋白芯片技术对血清差异蛋白进行同时检测，确定检测到的血清差异蛋白的浓度变化。
有益效果：本发明确定了可用于检测孤独症的血清差异蛋白组合。将所述血清差异蛋白组合用于制备检测孤独症的试剂，可以提高检测的客观性、特异性和准确性。
附图说明
图1为对照组和疾病组中RARS蛋白的ELISA实验结果对比图。
图2为对照组和疾病组中ACTL6B蛋白的ELISA实验结果对比图。
图3为对照组和疾病组中PRKAA1蛋白的ELISA实验结果对比图。
图4为对照组和疾病组中SLC25A12蛋白的ELISA实验结果对比图。
图5为对照组和疾病组中LIMK1蛋白的ELISA实验结果对比图。
图6为对照组和疾病组中POLR3C蛋白的ELISA实验结果对比图。
图7为对照组和疾病组中ARHGEF4蛋白的ELISA实验结果对比图。
图8为RARS蛋白、ACTL6B蛋白、PRKAA1蛋白、SLC25A12蛋白和LIMK1蛋白的受试者工作特征曲线。
具体实施方式
本发明提供一组血清差异蛋白组合在制备用于检测孤独症的试剂中的应用，为使本发明的目的、技术方案及效果更加清楚、明确，以下对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明提供一组血清差异蛋白组合在制备用于检测孤独症的试剂中的应用，其中，所述血清差异蛋白组合为RARS蛋白、ACTL6B蛋白、PRKAA1蛋白、SLC25A12蛋白和LIMK1蛋白中的任意3种或3种以上蛋白的组合。
血液由于采样方便且能较好反映机体病理生理过程而成为疾病标志物的最好来源之一。但要寻找到特异性好和准确性高，且能用于临床检测的血液蛋白标志物，有一定难度。既往研究表明孤独症属于复杂疾病，因此，在寻找其诊断标志物，尤其血液蛋白标志物时，很难寻找到单一的蛋白标志物。因此，本发明提 供上述血清差异蛋白组合用于制备检测孤独症的试剂。该试剂的应用能提高疾病检测的特异性和准确性，同时具有一定的客观性，优于单一疾病标志物。本发明提供的血清差异蛋白(共计5个)中的任意3种或3种以上蛋白组合即可作为孤独症检测标志物。此些标志物在用于检测孤独症时，具有一定的客观性、特异性和准确性。需说明的是，本发明的孤独症检测标志物的来源除血清外，还可以来自血浆。
作为本发明优选实施例，本发明上述血清差异蛋白组合为SLC25A12蛋白、LIMK1蛋白和RARS蛋白的组合。该组合蛋白用作孤独症检测标志物时具有较佳的客观性、特异性和准确性。
作为本发明优选实施例，本发明上述血清差异蛋白组合为SLC25A12蛋白、LIMK1蛋白和ACTL6B蛋白的组合。该组合蛋白用作孤独症检测标志物时同样具有较佳的客观性、特异性和准确性。
作为本发明优选实施例，本发明上述血清差异蛋白组合为PRKAA1蛋白、SLC25A12蛋白和LIMK1蛋白的组合。该组合蛋白用作孤独症检测标志物时同样具有较佳的客观性、特异性和准确性。
作为本发明优选实施例，本发明上述血清差异蛋白组合为RARS蛋白、ACTL6B蛋白、LIMK1蛋白和SLC25A12蛋白的组合。该组合蛋白用作孤独症检测标志物时同样具有一定的客观性、特异性和准确性。
作为本发明优选实施例，本发明上述血清差异蛋白为RARS蛋白、PRKAA1蛋白、SLC25A12蛋白和LIMK1蛋白的组合。该组合蛋白用作孤独症检测标志物时同样具有一定的客观性、特异性和准确性。
作为本发明优选实施例，本发明上述血清差异蛋白为RARS蛋白、ACTL6B蛋白、PRKAA1蛋白、SLC25A12蛋白和LIMK1蛋白的组合。该组合蛋白用作孤独症检测标志物时同样具有一定的客观性、特异性和准确性。
本发明提供一组血清差异蛋白组合在制备用于检测孤独症的试剂中的应用。其中，采集患者血清，通过高通量蛋白质组学方法确定血清中是否存在如上所述的血清差异蛋白组合。
进一步地，确定血清中存在血清差异蛋白的方法还包括：采用酶联免疫技术对血清差异蛋白进行逐个检测，确定检测到的血清差异蛋白的浓度变化。与现有 的孤独症诊断方法相比，本发明根据检测到的血清差异蛋白的浓度变化，可进一步提高检测的特异性、灵敏度和准确性。
进一步地，本发明确定血清中存在差异蛋白的方法还包括：采用蛋白芯片技术对血清差异蛋白进行同时检测，确定检测到的血清差异蛋白的浓度变化。与现有的孤独症诊断方法相比，本发明根据检测到的血清差异蛋白的浓度变化，可进一步提高检测的特异性、灵敏度和准确性。
下面通过具体实施例对本发明进行详细说明。
实施例1
本发明采用计算预测和实验验证相结合的方法，识别出可用于孤独症诊断的血液蛋白标志物：首先，通过对已有孤独症患者和正常人脑组织的转录组数据进行比较分析，获得孤独症相关的差异表达基因；其次，采用入血蛋白预测程序对孤独症相关基因编码的蛋白进行分泌入血液分析，得到孤独症相关的血液蛋白；然后，通过孤独症相关血液蛋白进行功能分析，挑选潜在的孤独症的血液蛋白标志物；最后，收集孤独症患者和正常人的血液样品，通过酶联免疫技术(ELISA)对这些蛋白进行实验验证。因此，本发明的技术方案在寻找孤独症的血液蛋白标志物方面，较传统的通过蛋白质组学方法灵敏度高、特异性好，符合“多、快、好、省”的原则。
具体来讲，本发明通过比较分析79个孤独症患者和正常人脑组织的转录组数据，识别出364个孤独症相关的差异表达基因。其中，59个基因编码的蛋白被预测能够分泌入血液，成为孤独症相关的血液蛋白。之后，通过对孤独症相关血液蛋白进行功能分析，7个蛋白被挑选出来成为潜在的孤独症血液蛋白标志物，并收集患者和正常人的血液样品进行了ELISA实验验证，实验结果详见图1-图7。该7个蛋白的计算预测与实验验证的结果比较详见表1。
表1. 7个孤独症潜在的血液蛋白标志物的计算预测和实验验证结果
Figure PCTCN2019097629-appb-000001
Figure PCTCN2019097629-appb-000002
通过统计分析，发现RARS,ACTL6B,PRKAA1,SLC25A12和LIMK1的蛋白浓度在孤独症患者和正常人的血液之间存在显著差异。进而，通过受试者工作特征曲线(receiver operating characteristic curve，ROC)分析发现，SLC25A12的曲线下面积(area under the curve,AUC)为0.976，敏感性为100％，特异性为88.2％，表明其具有很强的区分孤独症患者和正常人的能力。而其他4个蛋白LIMK1、RARS、ACTL6B和PRKAA1的AUC分别为0.898、0.862、0.793和0.768，请见图8。通过采集血清，对这5个蛋白逐个进行酶联免疫(ELISA)检测，或者通过蛋白芯片对这5个蛋白进行同时检测，根据蛋白表达的变化趋势可以对孤独症患者进行诊断。通过研究发现这5种蛋白与孤独症的发生和发展密切相关，其中，SLC25A12在线粒体功能和ATP合成中起重要作用，其单核苷酸多态性对患孤独症风险有显著影响；LIMK1能够刺激轴突的生长，在神经发育和突触可塑性中起作用，其与孤独症的发生有关；RARS是一种对RNA翻译至关重要的酶，其在髓鞘形成中起着重要作用；ACTL6B是孤独症的候选危险基因，具有神经元特异性染色质重塑和神经发育功能；PRKAA1是蛋白激酶A的催化亚基，在调节细胞能量代谢中起着关键作用，孤独症的退化与蛋白激酶A介导的蛋白磷酸化水平降低和细胞信号异常有关。
通过采集患者血清样品，对这5种蛋白逐个进行酶联免疫(ELISA)检测，或者通过蛋白芯片对这5种蛋白进行同时检测，根据蛋白表达的变化趋势可以对孤独症患者进行诊断。
综上所述，本发明通过采用计算预测和实验验证相结合的新型研究策略，从孤独症患者脑组织的转录组数据到血液蛋白质组数据进行映射分析，并结合ELISA实验，筛选出能够区分孤独症患者与健康对照的一组差异蛋白，所述血清差异蛋白组为RARS蛋白、ACTL6B蛋白、PRKAA1蛋白、SLC25A12蛋白和LIMK1蛋白，此组差异蛋白的任意3种或3种以上蛋白组合可用于制备检测孤独症的试剂，采取组合标志物的方式，能提高孤独症检测的准确性和特异性。
应当理解的是，本发明的应用不限于上述的举例，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，所有这些改进和变换都应属于本发明所附权利要求的保护范围。

Claims (4)

  1. 一组血清差异蛋白组合在制备用于检测孤独症的试剂中的应用，其特征在于，所述血清差异蛋白组合为RARS蛋白、ACTL6B蛋白、PRKAA1蛋白、SLC25A12蛋白和LIMK1蛋白中的任意3种或3种以上蛋白的组合。
  2. 根据权利要求1所述的应用，其特征在于，采集血清，通过高通量蛋白质组学方法确定血清中是否存在所述的血清差异蛋白组合。
  3. 根据权利要求2所述的应用，其特征在于，确定血清中存在血清差异蛋白组合还包括：采用酶联免疫技术对血清差异蛋白组合中的各个蛋白进行逐个检测，确定检测到的血清差异蛋白的浓度变化。
  4. 根据权利要求2所述的应用，其特征在于，确定血清中存在血清差异蛋白组合还包括：采用蛋白芯片技术对血清差异蛋白进行同时检测，确定检测到的血清差异蛋白的浓度变化。
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