CN116239665A - Ncf4在制备调控炎症小体激活的制剂中的应用和作为炎症性疾病的治疗靶点中的应用 - Google Patents
Ncf4在制备调控炎症小体激活的制剂中的应用和作为炎症性疾病的治疗靶点中的应用 Download PDFInfo
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Abstract
本发明提供了NCF4在制备调控炎症小体激活的制剂中的应用和作为炎症性疾病的治疗靶点中的应用，属于生物医药药技术领域。Ncf4基因缺失能特异性抑制NLRP3和AIM2炎症小体的激活，进而有效降低半胱氨酸蛋白酶‑1(Caspase‑1)的活化水平；NCF4蛋白的过表达能有效促进了NLRP3和AIM2炎症小体的激活。本发明首次证实NCF4分子在制备调控炎症小体激活的制剂中的新用途，可用于抑制或增强炎症小体的激活，进而使NCF4分子在作为炎症小体异常激活疾病(如炎性肠炎、结直肠癌、关节炎、糖尿病、系统性红斑狼疮等炎症性疾病等)治疗靶点中具有潜在制药价值。
Description
技术领域
本发明属于生物医药药技术领域，具体涉及NCF4在制备调控炎症小体激活的制剂中的应用和作为炎症性疾病的治疗靶点中的应用。
背景技术
炎症小体激活在宿主的炎症发生、抵抗病原体入侵，自身免疫性疾病和癌症的发生中都发挥重要作用。最为经典的炎症小体包括NLRP3和AIM2两种炎症小体，其激活分别通过识别不同的刺激物，最终导致细胞半胱氨酸蛋白酶-1(Caspase-1)的激活，从而诱导细胞产生成熟的白介素1β(IL-1β)，同时激活的Caspase-1可裂解消化道皮肤素D(GSDMD)，导致细胞焦亡的发生。炎症小体激活异常与多种疾病发生相关，例如炎性肠炎、结直肠癌和关节炎等，通过靶向炎症小体激活来治疗相关疾病的的药物研发越来越多。但是，目前现有技术还没有关于NCF4分子应用于制备抑制炎症小体激活的药物的记载或报道。
发明内容
有鉴于此，本发明的目的在于提供一种NCF4在制备调控炎症小体激活的制剂中的应用，通过抑制NCF4蛋白或Ncf4基因的表达具有抑制炎症小体激活的作用，过表达NCF4蛋白或Ncf4基因有利于促进炎症小体激活的作用。
本发明的目的还在于提供一种NCF4蛋白或Ncf4基因作为炎症性疾病的治疗靶点中的应用。
本发明提供了NCF4分子在制备调控炎症小体激活的制剂中的应用。
优选的，所述炎症小体包括NLRP3和/或AIM2。
优选的，所述NCF4分子包括NCF4蛋白和/或Ncf4基因。
优选的，所述NCF4蛋白和/或Ncf4基因或促进NCF4蛋白和/或Ncf4基因表达的试剂在制备炎症小体的激活剂中的应用。
优选的，所述试剂包括包含Ncf4基因的重组过表达载体或包含Ncf4基因的病毒。
优选的，用于敲除或抑制所述NCF4蛋白和/或Ncf4基因表达的试剂在制备炎症小体激活的抑制剂中的应用。
优选的，敲除所述Ncf4基因的方法为CRISPR-Cas9；敲降所述Ncf4基因表达的试剂为小干扰RNA；抑制所述NCF4蛋白功能的试剂为NCF4蛋白活性抑制剂PKC412。
本发明提供了NCF4分子作为炎症性疾病的治疗靶点中的应用，所述NCF4分子包括NCF4蛋白和/或Ncf4基因。
优选的，所述炎症性疾病包括以下至少一种疾病：炎性肠炎、结直肠癌、关节炎、糖尿病和系统性红斑狼疮。
优选的，所述NCF4蛋白的氨基酸序列如SEQ ID NO:1所示；
所述Ncf4基因的核苷酸序列如SEQ ID NO:2所示。
本发明提供了NCF4分子在制备调控炎症小体激活的制剂中的应用。本发明实施例结果表明，小鼠BMDM细胞中Ncf4基因的缺失能特异性抑制NLRP3和AIM2炎症小体的激活，进而有效降低半胱氨酸蛋白酶-1(Caspase-1)的活化水平；同时实验表明，小鼠BMDM细胞中NCF4蛋白的过表达能有效促进了NLRP3和AIM2炎症小体的激活，提高半胱氨酸蛋白酶-1的活化水平。可见，本发明首次证实NCF4分子在制备调控炎症小体激活的制剂中的新用途，可用于抑制或增强炎症小体的激活，进而使NCF4分子在作为炎症小体异常激活疾病(如炎性肠炎、结直肠癌、关节炎、糖尿病、系统性红斑狼疮等炎症性疾病等)治疗靶点中具有潜在制药价值。
附图说明
图1为WT对照组和Ncf4-/-组小鼠原代BMDM细胞进行炎症小体激活处理后，活化的Caspase1P20的表达情况对比图，其中a表示NLRP3炎症小体结果，b表示AIM2炎症小体结果；
图2为WT对照组和Ncf4-/-组小鼠原代BMDM细胞使用PKC412预处理后进行炎症小体激活处理，活化的Caspase1P20的表达情况对比图，其中a表示NLRP3炎症小体结果，b表示AIM2炎症小体结果；
图3为WTSi-Ctrl对照组和Si-Ncf4小鼠原代BMDM细胞进行炎症小体激活处理后，活化的Caspase1P20的表达情况对比图，其中a表示NLRP3炎症小体结果，b表示AIM2炎症小体结果；
图4为WT对照组和NCF4蛋白过表达组小鼠原代BMDM细胞进行NLRP3和AIM2炎症小体激活处理后，活化的Caspase1P20的表达情况对比图。
具体实施方式
本发明提供了NCF4分子在制备调控炎症小体激活的制剂中的应用。
本发明首次证实NCF4分子具有调控炎症小体激活状态的作用。所述炎症小体优选包括NLRP3和/或AIM2。所述NLRP3优选由脂多糖和三磷酸腺苷共同激活；所述AIM2优选由dsDNA激活。
在本发明中，所述NCF4分子优选包括NCF4蛋白和/或Ncf4基因。所述NCF4蛋白的氨基酸序列优选如SEQ ID NO:1(MALAQQLRSESDFEQLPDDVAVSANIADIEEKRGFTSHFVFVIEVKTKGGSKYLIYRRYRQFYALQSKLEERFGPESKNSPFTCSLPTLPAKVYMGAKQEIAETRIPALNAYMKNLLSLPVCVLMDPDVRIFFYQSAYDAEQVPQALRRLRPRTRKIKGVSPQGAIMDRMEAPRAEALFDFTGNSKLELSFKAGDVIFLLSKINKDWLEGTSQGATGIFPGSFVKILKDFPEDEDTTNWLRCYFYEDTGKTIKDIAVEEDLSSTPLFKDLLALMRREFQREDIALSYQDAEGDLVRLLSDEDVGLMVKQARGLPSQKRLFPWKLHVTQKDNYSVYNTVP)所示。所述Ncf4基因的核苷酸序列优选如SEQ ID NO:2(ATGGCCCTGGCCCAGCAGCTGCGATCAGAGAGCGACTTTGAGCAGCTTCCAGACGATGTGGCCGTCTCAGCCAACATCGCTGACATCGAGGAGAAGAGGGGCTTCACCAGCCACTTTGTTTTTGTCATCGAGGTCAAAACAAAAGGAGGGTCCAAGTATCTCATCTACCGCCGCTATCGCCAGTTCTACGCCCTGCAGAGCAAGCTGGAGGAGCGGTTTGGGCCAGAGAGCAAGAACAGCCCTTTCACCTGCAGCCTGCCCACATTGCCAGCCAAAGTCTACATGGGCGCAAAACAAGAGATCGCTGAGACTCGGATCCCGGCCCTCAATGCCTACATGAAGAACCTCCTGAGCCTGCCGGTCTGCGTGCTGATGGACCCCGACGTCAGGATCTTCTTCTATCAGTCTGCATACGATGCTGAGCAGGTGCCCCAGGCACTCCGCAGGCTCCGACCGCGCACGCGCAAAATCAAGGGTGTGTCTCCACAAGGGGCCATCATGGATCGCATGGAAGCGCCAAGAGCAGAGGCCTTGTTTGACTTCACTGGGAACAGCAAATTGGAGCTAAGTTTCAAAGCTGGAGATGTGATCTTCCTTCTCAGTAAGATCAACAAAGACTGGCTGGAGGGCACCTCCCAGGGAGCCACAGGCATCTTCCCAGGGTCCTTCGTGAAGATCCTTAAGGACTTTCCCGAGGACGAGGACACCACCAACTGGCTACGATGCTACTTCTATGAAGACACAGGCAAAACCATCAAGGACATTGCGGTGGAGGAGGACCTCAGCAGCACGCCCCTGTTCAAAGACCTGCTAGCGCTCATGAGGCGTGAGTTCCAGAGAGAAGACATTGCCCTTAGCTACCAGGATGCTGAGGGGGACTTGGTTAGGCTGCTGTCAGATGAGGATGTGGGACTCATGGTGAAGCAAGCCCGAGGCCTCCCTTCCCAGAAGCGCCTCTTCCCCTGGAAGCTGCATGTCACACAGAAGGACAACTACAGTGTCTACAACACTGTCCCCTGA)所示。
在本发明中，优选所述NCF4蛋白和/或Ncf4基因或促进NCF4蛋白和/或Ncf4基因表达的试剂在制备炎症小体的激活剂中的应用。所述试剂优选包括包含Ncf4基因的重组过表达载体(pCDH-Flag-NCF4)或包含Ncf4基因的病毒(使用293T细胞进行pCDH-Flag-NCF4慢病毒包装产生含Ncf4基因的病毒)。本发明实施例结果表明，与野生型细胞相比，通过原代BMDM细胞中过表达NCF4蛋白可显著提高炎症小体激活，显著提高Caspase-1的活化水平。
在本发明中，优选用于敲除或抑制所述NCF4蛋白和/或Ncf4基因表达的试剂在制备炎症小体激活的抑制剂中的应用。敲除所述Ncf4基因的方法为CRISPR-Cas9；抑制所述Ncf4基因表达的试剂包括小干扰RNA。抑制所述NCF4蛋白功能的试剂优选包括NCF4蛋白活性抑制剂PKC412。本发明实施例结果表明：(1)以Ncf4-/-小鼠原代BMDM细胞为对象经炎症小体刺激物处理，与野生型细胞相比，Ncf4-/-小鼠BMDM细胞可显著抑制NLRP3和AIM2炎症小体的激活，Caspase-1活化水平显著下降；(2)以进行Si-Ncf4敲降的小鼠原代BMDM细胞为对象经炎症小体刺激物处理，与Si-Ctrl细胞相比，Si-Ncf4敲降的小鼠BMDM细胞可显著抑制NLRP3和AIM2炎症小体的激活，Caspase-1活化水平显著下降；(3)以使用抑制剂PKC412预处理的小鼠原代BMDM细胞为对象经炎症小体刺激物处理，与未使用抑制剂预处理细胞相比，抑制剂处理的小鼠BMDM细胞可显著抑制NLRP3和AIM2炎症小体的激活，Caspase-1活化水平显著下降。
鉴于炎症小体异常激活往往导致炎症性疾病，同时NCF4分子具有调控炎症小体激活状态的作用，因此本发明提供了NCF4分子作为炎症性疾病的治疗靶点中的应用，所述NCF4分子包括NCF4蛋白和/或Ncf4基因。
在本发明中，用于敲除或抑制所述NCF4蛋白和/或Ncf4基因表达的试剂在制备预防和/或炎症性疾病药物中的应用。敲除所述Ncf4基因的优选方法为CRISPR-Cas9(gRNA1-AGGUGGAUACGUUCAUAUGAGGG，SEQ ID NO:3；gRNA2-GAAGUGACCCUCUCCUGUCAGG，SEQ ID NO:4)，敲降所述Ncf4基因表达的试剂优选包括小干扰RNA(序列：CCCUCAAUGCCUACAUGAA，SEQID NO:5；AGCAAGAACAGCCCUUUCA，SEQ ID NO:6；GUUCCAGAGAGAAGACAUU，SEQ ID NO:7)，抑制所述NCF4蛋白功能的试剂优选包括抑制PKC412(MedcheExpress,120685)。
在本发明中，所述炎症性疾病优选包括以下至少一种疾病：炎性肠炎、结直肠癌、关节炎、糖尿病和系统性红斑狼疮。现有技术(参见参考文献1～8)报道由于炎性肠炎、结直肠癌、关节炎、糖尿病和系统性红斑狼疮等疾病的发生发展与炎症小体的异常激活有关，通过炎症小体也是治疗上述疾病的药物靶点，本发明通过采用NCF4分子来调整炎症小体的激活状态进而能够达到治疗上述疾病的药效。
参考文献：
1.张霁.基于NLRP3炎症小体信号通路的隔药灸治疗克罗恩病的作用机制研究[D].上海中医药大学,2019.000112.
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7.苗晋鑫,彭孟凡,任伟宏,苗明三.NLRP3炎症小体在糖尿病及并发症的作用及中药经NLRP3对其影响研究进展[J].中国实验方剂学杂志,2022,28(16):254-260.
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下面结合实施例对本发明提供的NCF4在制备调控炎症小体激活的制剂中的应用和作为炎症性疾病的治疗靶点中的应用进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
实施例1
比较野生型(WT)小鼠和Ncf4-/-小鼠原代BMDM细胞中NLRP3和AIM2炎症小体的激活试验
1.Ncf4-/-小鼠和WT小鼠分别购自赛业生物和维通利华公司。
2.原代BMDM细胞的制备方法
将适龄成年(如6～8周)的Ncf4-/-小鼠和WT小鼠安乐死处理。在无菌条件下分离股骨、胫骨并置于PBS缓冲液中，用手术刀刮去骨表面的肌肉、软骨及骨骺，将骨两端切开露出骨髓腔后，用1mL注射器吸取DMEM-F12培养基冲洗骨髓腔，收集细胞，细胞吹打均匀后，计数并调整细胞密度为1～2Million/mL，在DMEM-F12完全培养基中添加20ng/mL的M-CSF生长因子，将细胞接种在细胞培养板中，在5％CO2、37℃的CO2培养箱内培养，静置培养5天后收取贴壁细胞进行后续试验。
3.原代BMDM细胞的敲降方法
BMDMs培养养5天后刮取细胞并收集到50ml的无菌离心管中，用50mlPBS(无Ca2+和Mg2+)重悬吹打混匀计数，取适量细胞离心加入适量siRNA(si-Ctrl和si-Ncf4)用T液重悬，进行电转染后将细胞悬液滴入含20ng/mL的M-CSF生长因子的DMEM-F12完全培养基中，混匀后按1Million/mL细胞重悬液/孔的量接种到12孔板中，在5％CO2、37℃的CO2培养箱内培养40～44h取贴壁细胞进行后续试验。
4.炎症小体的激活处理
采用炎症小体刺激物分别处理NLRP3和AIM2炎症小体，其中激活NLRP3炎症小体的刺激物为脂多糖(LPS)和三磷酸腺苷(ATP)。激活AIM2炎症小体的刺激物为双链DNA(dsDNA)。具体处理方法如下：
用终浓度为500ng/mL的LPS刺激4h后，然后用终浓度5mM的ATP分别刺激0.5h和1h，用Westernblot检测培养上清中半胱氨酸蛋白酶-1激活切割产物Caspase-1P20的表达水平(炎症小体激活时，最为关键的环节是在胞质中形成ASCSpeck并大量募集并切割Caspase-1，活化的Caspase-1p20会促进炎性因子IL-1β和IL-18的成熟和释放以及细胞焦亡发生)，当与WT组相比，实验组呈显著性差异，说明激活NLRP3炎症小体。
用X-fect转染终浓度为1.5μgdsDNA(常规的pCDH质粒DNA)分别刺激1h和2h，用Westernblot检测培养上清中半胱氨酸蛋白酶-1激活切割产物Caspase-1P20的表达水平，当与WT组相比，实验组细胞检测结果呈显著性差异，说明激活AIM2炎症小体。
同时，选用未添加刺激物的培养上清(Med)用作0h对照组。
结果表明，在小鼠原代BMDM细胞中，Ncf4-/-组细胞与WT组细胞相比，在LPS+ATP、dsDNA处理后其活化的Caspase-1P20的表达均显著下降(图1，其中Media组代表未添加刺激物的培养上清对照组，Casp1代表Caspase-1，Med代表Media)。
Si-Ncf4敲降组的细胞与Si-Ctrl组细胞相比，在LPS+ATP、dsDNA处理后其活化的Caspase-1P20的表达均显著下降(图2)。
抑制剂处理的细胞与未使用抑制剂预处理细胞相比，在LPS+ATP、dsDNA处理后其活化的Caspase-1P20的表达均显著下降(图3)。
NCF4蛋白过表达组细胞与对照组WT组细胞相比，在LPS+ATP、dsDNA处理后其活化的Caspase-1P20的表达均显著上升(图4)。
以上结果表明，在Ncf4-/-小鼠BMDM细胞中可显著抑制NLRP3和AIM2炎症小体的激活，而NCF4蛋白过表达可以显著促进NLRP3和AIM2炎症小体的激活。
以上实施例结果可知，本发明首次证实NCF4分子具有调控炎症小体激活状态的作用，过表达NCF4分子可以显著促进炎症小体的激活，而敲除或抑制NCF4分子可以显著抑制炎症小体的激活，因此本发明提供了NCF4分子在制备调控炎症小体激活的制剂中的新用途。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.NCF4分子在制备调控炎症小体激活的制剂中的应用。
2.根据权利要求1所述应用，其特征在于，所述炎症小体包括NLRP3和/或AIM2。
3.根据权利要求1所述应用，其特征在于，所述NCF4分子包括NCF4蛋白和/或Ncf4基因。
4.根据权利要求3所述应用，其特征在于，所述NCF4蛋白和/或Ncf4基因或促进NCF4蛋白和/或Ncf4基因表达的试剂在制备炎症小体的激活剂中的应用。
5.根据权利要求4所述应用，其特征在于，所述试剂包括包含Ncf4基因的重组过表达载体或包含Ncf4基因的病毒。
6.根据权利要求3所述应用，其特征在于，用于敲除或抑制所述NCF4蛋白和/或Ncf4基因表达的试剂在制备炎症小体激活的抑制剂中的应用。
7.根据权利要求6所述应用，其特征在于，敲除所述Ncf4基因的方法为CRISPR-Cas9；
敲降所述Ncf4基因表达的试剂为小干扰RNA；
抑制所述NCF4蛋白功能的试剂为NCF4蛋白活性抑制剂PKC412。
8.NCF4分子作为炎症性疾病的治疗靶点中的应用，所述NCF4分子包括NCF4蛋白和/或Ncf4基因。
9.根据权利要求8所述应用，其特征在于，所述炎症性疾病包括以下至少一种疾病：炎性肠炎、结直肠癌、关节炎、糖尿病和系统性红斑狼疮。
10.根据权利要求3～9中任意一项所述应用，其特征在于，所述NCF4蛋白的氨基酸序列如SEQ ID NO:1所示；
所述Ncf4基因的核苷酸序列如SEQ ID NO:2所示。
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