CN111996246B - CircPPM1F作为T1DM诊疗靶点的用途 - Google Patents

CircPPM1F作为T1DM诊疗靶点的用途 Download PDF

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CN111996246B
CN111996246B CN202010106933.4A CN202010106933A CN111996246B CN 111996246 B CN111996246 B CN 111996246B CN 202010106933 A CN202010106933 A CN 202010106933A CN 111996246 B CN111996246 B CN 111996246B
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周玉峰
张彩艳
韩晓
杨兰
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Abstract

本发明公开了circPPM1F作为T1DM诊疗靶点的用途。circPPM1F作为诊断标志物在制备T1DM辅助诊断试剂中的应用。抑制circPPM1F的试剂在制备治疗T1DM的药物中的应用。一种治疗T1DM的药物组合物，包含circPPM1F的siRNA和药物载体。circPPM1F在T1DM患者的PBMC中呈明显高表达，ROC曲线表明circPPM1F作为T1DM的诊断marker有着相当的可信度。circPPM1F正向调节巨噬细胞TLR‑MyD88通路的激活，诱导炎症因子表达，进而损伤胰岛细胞功能。这提示circPPM1F可能作为T1DM预防及治疗的一个新靶点。

Description

CircPPM1F作为T1DM诊疗靶点的用途
技术领域
本发明属于医药生物领域，涉及circPPM1F作为T1DM诊疗靶点的用途。
背景技术
1型糖尿病(type 1diabetes mellitus，T1DM)又称胰岛素依赖性糖尿病，是由T细胞介导的自身免疫系统对胰岛β细胞进行特异性损伤而引起的一种器官特异性的自身免疫疾病[1]。T1DM多发生于青少年时期，临床症状较严重，且近年来该病的发病率呈逐年上升趋势，严重危害患者的生活质量及身心健康。T1DM的致病机理非常复杂，胰岛β细胞自身抗原，机体免疫系统的T细胞、B细胞、巨噬细胞、树突状细胞以及由这些免疫细胞所分泌的细胞因子和炎症因子等在T1DM的发病过程中起到了非常重要的作用[2-4]。
在T1DM的发病过程中，巨噬细胞是最早浸润胰岛的细胞之一，提示巨噬细胞在T1DM发病过程中发挥着重要作用。巨噬细胞作为一类功能多样性的免疫细胞，其功能依赖于激活状态，其中由LPS和IFN-γ等激活的M1型巨噬细胞可增强炎症反应、促进T1DM的发生[5]，而与免疫调节和修复相关的M2型巨噬细胞则控制炎症，减轻自身免疫反应，调节T1DM的病理过程。Calderon等研究证明，在非肥胖糖尿病(non-obese diabetic,NOD)小鼠体内，采用氯磷酸盐脂质体清除M1型巨噬细胞，可减轻胰岛炎并控制疾病进程[6]。同时研究发现，在炎细胞浸润的胰岛中，巨噬细胞以M1型为主，其产生的细胞因子包括IL-1β、TNF-α和IFN-γ等，IL-1β和TNF-α联合IFN-γ可诱导胰岛β细胞凋亡[7]。此外，M1型巨噬细胞也可通过诱导Th1/Th17亚群失衡或分泌炎性细胞因子改变细胞因子微环境，从而参与包括T1DM在内的多种自身免疫病的发生[8]。因此研究巨噬细胞激活的调控机制，对于探究T1DM的发病机制、诊疗和预防措施都有着十分重要的意义。
在最近几年，非编码RNA(non-coding RNA)成为基因组中调控基因表达的研究新热点。环状RNA(circular RNA，circRNA)是一类经反向剪接后、由3’末端和5’末端共价结合形成的环状非编码RNA分子。高通量测序发现数千个circRNA广泛存在于多种生物细胞中，具有结构稳定、序列保守及细胞或组织特异性表达等特征[9,10]。circRNA在调控基因表达、翻译蛋白、吸附miRNA、与RNA结合蛋白(RBP)形成复合物等多个层面上参与细胞分化和个体发育等重要生命过程，揭示其在人类的多种疾病的调控过程中起到极其重要的作用，有在未来成为疾病的新的检测标志物的潜力[11-14]。近来的研究表明，circRNA也参与到T1DM等自身免疫性疾病的发生发展过程。例如研究发现环状RNA CDR1as在胰岛细胞中通过阻碍miR-7的功能从而影响糖尿病患者的胰岛素分泌和胰岛β细胞的更新[15]。
发明内容
本发明的目的是针对现有技术的上述不足，提供circPPM1F作为T1DM诊断和治疗靶点的用途。
circPPM1F作为诊断标志物在制备T1DM辅助诊断试剂中的应用。
检测circPPM1F表达量的试剂在制备T1DM辅助诊断试剂中的应用。
所述的检测circPPM1F表达量的试剂优选circPPM1F的特异性引物。
circPPM1F作为治疗靶点在制备治疗T1DM的药物中的应用。
circPPM1F作为靶点在制备预防T1DM的药物中的应用。
抑制circPPM1F的试剂在制备治疗T1DM的药物中的应用。
所述的抑制circPPM1F的试剂优选circPPM1F的siRNA。
circPPM1F作为治疗靶点在筛选治疗T1DM的药物中的应用。
一种治疗T1DM的药物组合物，包含circPPM1F的siRNA和药物载体。
有益效果：
本发明在T1DM患者PBMC中，通过circRNA microarray分析，得到58个差异表达的circRNA，其中高表达的circPPM1F与炎症因子IL-6和IL-1β呈正相关，在巨噬细胞中，circPPM1F通过激活NF-κB信号正向调控TLR-MyD88通路，进而促进炎症因子的表达，最终抑制胰岛细胞增殖，并促进凋亡，介导T1DM的发生发展。
circPPM1F在T1DM患者的PBMC中明显高表达，与炎症因子IL-6和IL-1β的表达水平具有正相关性，同时ROC曲线表明circPPM1F作为T1DM的诊断marker有着相当的可信度。另外，circPPM1F在机制上参与NF-κB信号通路的激活，抑制circPPM1F可减缓巨噬细胞的炎症反应，circPPM1F过表达会明显抑制胰岛细胞MIN6增殖，促进凋亡，损伤胰岛细胞功能。因此circPPM1F可能作为一个新的药物干预靶点，或者结合PD-L1等检查点抑制剂，为诊断和治疗T1DM带来新的希望。
附图说明
图1.儿童T1DM患者PBMC中高表达的circPPM1F与T1DM发展相关。(A)热图和火山图表示对儿童T1DM患者的PBMC进行circRNA microarray分析；(B，D)RT-qPCR检测circPPM1F、IL-6和IL-1β在T1DM和正常人PBMC中的表达水平；(C)ROC曲线评价circPPM1F区分T1DM患者和正常人的可信度；(E)circPPM1F表达水平与IL-6和IL-1β的相关性分析。
图2.circPPM1F通过激活NF-κB通路促进LPS诱导的巨噬细胞激活。(A)circPPM1F在转录本上的定位及PCR测序；(B-D)在PMA诱导THP1转化而成的巨噬细胞中，使用siRNA降低circPPM1F的表达水平，LPS刺激细胞，qPCR检测LPS诱导的巨噬细胞激活相关基因的表达水平，western blot检测检测LPS-MyD88通路下游激活的p65、JNK、p38和ERK磷酸化表达水平。
图3.circPPM1F通过促进LPS诱导的巨噬细胞激活抑制胰岛细胞增殖。(A)CCK-8法检测共培养后MIN6细胞增殖情况；(B)流式细胞术检测共培养后MIN6细胞凋亡情况。
具体实施方式
材料和方法：
1细胞培养和转染
人单核细胞THP1购自ATCC，小鼠胰岛细胞MIN6和巨噬细胞Raw264.7购自FDCC。THP1和MIN6培养基为1640(含10％胎牛血清，100U/mL青霉素-链霉素)，MIN6培养基需再加50uM 2-巯基乙醇，Raw264.7培养基为DMEM(含丙酮酸钠，10％胎牛血清)。传代时，MIN6用0.05或0.25mM含EDTA胰酶消化，Raw264.7用细胞刮，THP1为悬浮细胞。37℃5％CO2培养。
siRNA按照LipoRNAiMAX说明书方法转染，质粒按照Lipo2000说明书转染。circPPM1F的siRNA及相应的阴性对照来自上海吉玛公司。
2 RNA抽提和逆转录
将THP1诱导的巨噬细胞培养于24孔板，用LipoRNAiMAX脂质体转染方法转染circPPM1F的siRNA(200nM)及阴性对照(NC)，48h后加入LPS(200ng/mL，RD公司)，刺激3h后，除去上清，使用TRIzol(Invitrogen公司产品)抽提RNA。
mRNA和circRNA的逆转录采用PrimeScript RT reagent kit(TaKaRa公司)，加样体系为10uL，逆转录反应条件为37℃15min，85℃5s。
3实时荧光定量PCR(Real-time PCR)
在LightCycler 480(Roche公司)上进行实时荧光定量PCR操作。
4免疫印迹实验(western blot)
将THP1诱导的巨噬细胞培养于6孔板，用LipoRNAiMAX脂质体转染方法转染circPPM1F的siRNA(200nM)及阴性对照(NC)，48h后加入LPS处理0min，5min与15min，用RIPABuffer(Thermo公司)裂解法抽提总蛋白。采用抗体p-p65(CST公司)，p-65(CST公司)，β-tubulin(abcam公司)。
5人巨噬细胞或Raw264.7与MIN6共培养
将THP1诱导的巨噬细胞或Raw264.7培养于6孔板，转染circPPM1F siRNA或过表达质粒3D5-circPPM1F 48h后加LPS刺激20h；收上清，4℃，3,000rpm离心30min，此为条件培养基。将MIN6细胞铺于96孔板，1.8×10^3/孔，24h后，条件培养基与完全培养基1:1处理细胞，CCK-8法检测处理0h，24h，48h和72h的吸光度。另外，将MIN6细胞铺于6孔板，1×10^5/孔，24h后，条件培养基与完全培养基1:1处理细胞，48h后加500μM H2O2处理15h，收细胞，Annexin V-FITC/PI染色后，利用流式细胞仪检测细胞凋亡情况。
实施例1筛选发现儿童T1DM患者PBMC中高表达的circPPM1F与T1DM发展相关
我们通过收集4例儿童T1DM患者和4例相同年龄段正常儿童的PBMC细胞，并进行circRNA microarray分析，发现有27个circRNA表达上调，31个表达下调(图1A)。我们筛选数个表达显著的circRNA在40例患者PBMC样本中进行RT-qPCR实验验证，发现相比于正常样本，只有circPPM1F(hsa_circ_0062444)显著高表达，(图1B)，感受性曲线(ROC)面积为0.8041(图1C)。同时我们也检测了40例样本中炎性因子IL-6和IL-1β的表达呈显著上调(图1D)，并且与circPPM1F表达呈正相关(图1E)。这些结果揭示了PBMC中的高表达的circPPM1F极有可能参与到儿童T1DM的发生发展过程中。
实施例2 circPPM1F通过激活NF-κB通路促进LPS诱导的巨噬细胞激活
我们通过生物信息学分析及PCR产物测序，确定了circPPM1F在转录本上的定位，来源于PPM1F的第6-8三个外显子(图2A)。采用siRNA降低circPPM1F表达，随后LPS刺激巨噬细胞，qPCR检测发现，降低circPPM1F的表达后，能够明显抑制LPS诱导的巨噬细胞激活相关基因(IL-1β、TNF-α和CXCL10)的表达水平(图2B)；同时通过免疫印迹检测，我们也验证了敲低circPPM1F能够明显降低LPS激活的p65的磷酸化水平(图2C)，但不影响JNK、p38和ERK的磷酸化水平(图2D)。以上结果表明circPPM1F通过激活NF-κB信号通路正向调控LPS诱导的巨噬细胞激活。
实施例3 circPPM1F通过促进LPS诱导的巨噬细胞激活抑制胰岛细胞增殖
为了体外模拟巨噬细胞中异常表达的circPPM1F对胰岛细胞的影响，我们收集THP1诱导的人巨噬细胞和鼠巨噬细胞Raw264.7中下调或过表达circPPM1F后的条件培养基，然后用来处理MIN6细胞。CCK-8法表明，巨噬细胞低表达circPPM1F能明显促进MIN6细胞增殖，而高表达则抑制MIN6增殖(图3A)。另外，流式细胞术表明巨噬细胞低表达circPPM1F能显著抑制MIN6细胞凋亡，而高表达则促进MIN6凋亡(图3B)。
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Claims (5)

1.检测circPPM1F 表达量的试剂在制备一型糖尿病T1DM辅助诊断试剂中的应用。
2.根据权利要求1所述的应用，其特征在于所述的检测circPPM1F 表达量的试剂为circPPM1F的特异性引物。
3.抑制circPPM1F表达量的试剂在制备治疗一型糖尿病T1DM的药物中的应用。
4.根据权利要求3所述的应用，其特征在于所述的抑制circPPM1F的试剂为circPPM1F的siRNA。
5.circPPM1F作为治疗靶点在筛选治疗一型糖尿病T1DM的药物中的应用，所述治疗是指抑制circPPM1F的表达量来实现。
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CN106399309A (zh) * 2016-08-24 2017-02-15 江苏省省级机关医院 一种长非编码rna及其在诊断/治疗t2dm中的应用
CN109852688A (zh) * 2019-04-02 2019-06-07 中国药科大学 一种2型糖尿病的诊断引物及试剂盒、以及非编码rna分子标志物的应用

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CN106399309A (zh) * 2016-08-24 2017-02-15 江苏省省级机关医院 一种长非编码rna及其在诊断/治疗t2dm中的应用
CN109852688A (zh) * 2019-04-02 2019-06-07 中国药科大学 一种2型糖尿病的诊断引物及试剂盒、以及非编码rna分子标志物的应用

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