CN115177730B - Ptpn22及其表达抑制剂的新用途 - Google Patents
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Abstract
本发明属于生物技术领域，具体公开PTPN22及其表达抑制剂的新用途。PTPN22表达抑制剂在制备治疗心力衰竭疾病竭药物中的应用。检测PTPN22表达的制剂在制备筛查诊断心力衰竭疾病产品中的应用。PTPN22表达抑制剂在制备治疗ZAP‑70Y292去磷酸化诱发疾病中的应用。本发明发现了PTPN22在慢性心力衰竭患者外周血CD4+T细胞中升高，通过对PTPN22蛋白表达情况的检测可以用于慢性心力衰竭患者的辅助诊断；PTPN22蛋白可应用于慢性心力衰竭检测试剂盒，进一步丰富慢性心力衰竭诊断及预后检测的位点。
Description
技术领域
本发明属于生物技术领域，尤其涉及PTPN22及其表达抑制剂的新用途。
背景技术
心力衰竭是指心脏失去与代谢组织匹配的泵血能力的病理状态，以间质纤维化、心室顺应性降低以及心室扩张为主要特征。在慢性心力衰竭中，持续的慢性炎症反应对机体的异常调节，会导致左室收缩功能异常、心室重塑以及心脏纤维化。心力衰竭包括急性心力衰竭和慢性心力衰竭，慢性心力衰竭中又有非缺血性心力衰竭和缺血性心力衰竭等不同类型病症。
既往研究探索了蛋白酪氨酸磷酸酶非受体型22(Protein tyrosinephosphatase,nonreceptor type,22，PTPN22)在T细胞激活和自身免疫性疾病中的作用。PTPN22的作用底物包括Zeta链相关蛋白激酶70kDa(Zeta-chain–associated proteinkinase of 70kDa，ZAP-70)、淋巴细胞特异性酪氨酸蛋白激酶等多个磷酸化位点，PTPN22对其底物进行去磷酸化，导致底物磷酸化减少。ZAP-70磷酸化后可以结合至TCR-CD3ζ，参与TCR信号的激活。TCR早期信号的激活可以促进CD4+T细胞向调节性T细胞(Tregs) 转化。然而，过高的TCR信号激活会导致Tregs的分化减少。Tregs的减少已被证明与慢性心力衰竭的不良预后相关。
发明内容
针对上述问题，本发明提供PTPN22及其表达抑制剂的新用途，主要为了研究PTPN22新用途，主要为了探索PTPN22在心力衰竭疾病的诊断、治疗中的应用前景。
为了解决上述问题，本发明采用如下技术方案：
PTPN22表达抑制剂在制备治疗心力衰竭疾病竭药物中的应用。
在一些方式中，所述PTPN22表达抑制剂包括siRNA。
在一些方式中，所述心力衰竭疾病为慢性心力衰竭。
在一些方式中，所述慢性心力衰竭包括非缺血性心力衰竭。
检测PTPN22表达的制剂在制备筛查诊断心力衰竭疾病产品中的应用。
在一些方式中，所述心力衰竭疾病为慢性心力衰竭。
在一些方式中，所述慢性心力衰竭包括非缺血性心力衰竭。
PTPN22表达抑制剂在制备治疗ZAP-70Y292去磷酸化诱发疾病中的应用。
PTPN22在制备ZAP-70Y292去磷酸化产品中非诊断治疗的应用。
本发明的有益效果是：
发现了PTPN22在慢性心力衰竭患者外周血CD4+T细胞中升高，通过对 PTPN22蛋白表达情况的检测可以用于慢性心力衰竭患者的辅助诊断；为慢性心力衰竭的发病机理提供重要线索，对慢性心力衰竭的免疫诊断和治疗具有重要意义；PTPN22蛋白可应用于慢性心力衰竭检测试剂盒，进一步丰富慢性心力衰竭诊断及预后检测的位点。
附图说明
图1：研究人群基本临床特征表；
图2：CHF患者CD4+T细胞中PTPN22表达明显升高；
图3：CHF患者外周血CD4+T细胞PTPN22表达与临床指标的相关性；
图4：siRNA-PTPN22转染CD4+T细胞后，Tregs分化减少；
图5：PTPN22通过去磷酸化ZAP-70Y292调控CD4+T细胞中TCR早期信号。
具体实施方式
下面对本发明做进一步说明：
本部分第一方面介绍PTPN22在制备抗心力衰竭药物中的用途：
PTPN22表达抑制剂在制备治疗心力衰疾病竭药物中的应用。
所述PTPN22表达抑制剂包括siRNA等，其他能够实现抑制或干扰表达的手段均等同。
其中，所述心力衰竭疾病包括慢性心力衰竭，通过抑制PTPN22表达针对慢性心力衰竭具有更好的治疗效果。
慢性心力衰竭主要是慢性原发性心肌病变和心室因长期压力或容量负荷过重，使心肌收缩力减弱，不能维持心排血量。慢性心力衰竭相关衰竭病症中部分属于非缺血性心力衰竭，另有部分属于缺血性心力衰竭。PTPN22表达抑制剂对非缺血性心力衰竭的治疗效果更加明显。
本部分第二方面介绍PTPN22在制备检测产品中的用途：
其中之一，PTPN22在制备筛查心力衰竭产品中的用途：
检测PTPN22表达的制剂在制备筛查诊断心力衰竭疾病产品中的应用。
检测PTPN22表达情况即可得知心力衰竭的严重程度，心力衰竭严重程度提升也会伴随PTPN22表达增加。
其中，所述心力衰竭疾病包括慢性心力衰竭。
更进一步的，所述慢性心力衰竭包括非缺血性心力衰竭和缺血性心力衰竭。其中，PTPN22表达情况与非缺血性心力衰竭的联系更加紧密，通过检测 PTPN22的表达可以更快速准确的检测非缺血性心力衰竭。PTPN22表达情况与缺血性心力衰竭的关联度比非缺血性心力衰竭关联度低。
其中之二，检测PTPN22表达的制剂在制备检测总酪氨酸磷酸化和/或 ZAP-70Y292的磷酸化水平检测产品中的应用。总酪氨酸磷酸化水平与PTPN22 表达水平正相关，ZAP-70Y292的磷酸化与PTPN22表达水平负相关。由此，通过检测所得的PTPN22表达水平即可得知总酪氨酸磷酸化水平、PTPN22表达水平的变化情况。并且，在实验中也整体性的验证了相应的函数关系，尤其是图5中也公开了相应的系数，可以据此进行数值分析，当然为了更准确的进行计算，还需要优化相应的公式。
检测PTPN22表达的制剂包括PCR、ELISA等检测，其中检测PTPN22表达的制剂不局限于一种特定的试剂，凡是能够检测PTPN22表达的产品均在此范围内。
本部分第三方面介绍PTPN22在ZAP-70Y292磷酸化调节产品中的用途：
PTPN22表达抑制剂在制备治疗ZAP-70Y292去磷酸化诱发疾病中的应用。 ZAP-70Y292去磷酸化诱发疾病包括CD4+T细胞分化异常引发的心力衰竭等。
PTPN22在制备ZAP-70Y292去磷酸化产品中非诊断治疗的应用。经过验证可知，PTPN22可以抑制ZAP-70Y292的磷酸化水平。其主要作用于一些非疾病治疗的环境，比如作为一些生物调节制剂。
本部分第四方面结合具体的实验项目作出进一步介绍：
实验准备
样本收集：在收集到40例慢性心力衰竭的患者，11例健康对照。所有参与本发明研究的成员均签署了知情同意书。发明人采集获得上述成员的外周血样本。
临床资料收集：发明人对上述慢性心力衰竭衰竭患者及健康对照的临床基本资料进行了采集，包括年龄、性别、纽约心脏协会(New York Heart Association，NYHA)分级、左心室射血分数(left ventricular ejection fraction，LVEF)、左心室舒张末期容积(leftventricular end-diastolic diameter，LVEDD)、B型钠尿肽(Type B natriureticpeptide，BNP)，如图 1中研究人群基本临床特征表所示。
结果分析
流式检测PTPN22表达：
通过流式细胞术检测上述外周血样本中CD4+T细胞的PTPN22蛋白表达水平。结果显示，相较于健康对照，慢性心力衰竭组外周血CD4+T细胞中PTPN22 明显升高，且两者正相关(图2)。
外周血CD4+T细胞中PTPN22表达与临床指标的关联分析：
采取Pearson’s关联性分析发现，慢性心力衰竭(CHF)患者外周血CD4+T 细胞中PTPN22表达量与血清BNP含量呈正相关(图3中A)，与LVEF呈负相关，与LVEDD呈正相关(图3中B、C)，这些相关性在非缺血性心力衰竭(NIHF) 中更为明显，前述的相关性在缺血性心力衰竭(IHF)中也同样存在。这一结果提示外周血CD4+T细胞中PTPN22表达升高与慢性心力衰竭患者的严重程度及心功能下降明显相关。
减少慢性心力衰竭患者外周血CD4+T细胞中PTPN22表达后Tregs分化增加：
构建了针对PTPN22的小干扰RNA(siRNA),并使用慢病毒进行转染，以降低非缺血性心衰患者外周血CD4+T细胞中PTPN22的表达(图4中A)。随后采用流式细胞术检测CD4+T细胞中Tregs的比例，发现转染siRNA-PTPN22组的Tregs比例增加(图4中B)。说明PTPN22的增加可减少Tregs的分化，从而可能对慢性心力衰竭患者的预后产生影响。
PTPN22通过去磷酸化ZAP-70Y292调控TCR早期信号：
总酪氨酸磷酸化(pTyr)反映TCR早期信号激活强度。ZAP-70 Y319和 ZAP-70 Y292被报道是PTPN22的可能作用位点。在分离慢性心力衰竭患者外周血单个核细胞后，使用CD3/CD28 mAb模拟TCR激活信号，在刺激5分钟时收取细胞，通过流式细胞术检测PTPN22表达和CD4+T细胞的总酪氨酸、ZAP-70 Y319和ZAP-70 Y292的磷酸化水平。如图5中，通过Pearson’s相关性分析发现在慢性心力衰竭组中，PTPN22与总酪氨酸磷酸化呈正相关，与ZAP-70 Y292的磷酸化水平呈负相关，这一趋势在非缺血性和缺血性病因引起的心力衰竭中均保持一致。这一结果提示PTPN22可能通过去磷酸化ZAP-70 Y292这一酪氨酸位点调控慢性心力衰竭患者外周血CD4+T细胞的TCR激活，从而对 CD4+T细胞的分化和生物学功能产生影响。
在上述实验研究的基础上，PTPN22在心力衰竭患者外周血CD4+T细胞中的表达及其应用，主要发现CD4+T细胞中PTPN22升高与心力衰竭患者临床指标的相关性，并填补了慢性心力衰竭的免疫一个方面的漏缺。
本领域的技术人员可以明确，在不脱离本发明的总体精神以及构思的情形下，可以做出对于以上实施例的各种变型。其均落入本发明的保护范围之内。本发明的保护方案以本发明所附的权利要求书为准。
Claims (2)
1.检测PTPN22表达情况的制剂在制备检测慢性心力衰竭严重程度的产品的应用，其中，PTPN22表达水平与慢性心力衰竭严重程度正相关，所述PTPN22源自慢性心力衰竭患者外周血CD4+T细胞。
2.根据权利要求1所述的应用，其中，检测PTPN22表达情况的制剂包括用于PCR、ELISA检测的试剂。
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