CN115364223A - 作用于stat 6靶点的物质成分在制备治疗慢性瘙痒症的药物中的应用 - Google Patents
作用于stat 6靶点的物质成分在制备治疗慢性瘙痒症的药物中的应用 Download PDFInfo
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- CN115364223A CN115364223A CN202210987238.2A CN202210987238A CN115364223A CN 115364223 A CN115364223 A CN 115364223A CN 202210987238 A CN202210987238 A CN 202210987238A CN 115364223 A CN115364223 A CN 115364223A
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了一种作用于STAT 6靶点的物质成分在制备治疗慢性瘙痒症的药物中的应用,旨在解决慢性瘙痒症缺乏有效的治疗药物的技术问题。本发明通过药物特异性抑制STAT 6酪氨酸641(Y641)的磷酸化进而达到改善和治疗慢性瘙痒症的作用。本申请首次发现以STAT6为靶点设计的抑制药物可以一方面通过调控其下游信号分子IL‑13和IL‑4阻遏外周神经至中枢神经的痒觉环路,缓解瘙痒信号的传递和病灶部位的炎症反应;另一方面可以调节皮肤角质形成细胞的屏障功能,上调皮肤屏障相关基因FLG和IVL转录表达,防止皮肤屏障功能的进一步恶化,为特应性皮炎和慢性瘙痒症提供了新的治疗措施。
Description
技术领域
本发明涉及药物技术领域,具体涉及一种作用于STAT 6靶点的物质成分在制备治疗慢性瘙痒症的药物中的应用。
背景技术
慢性痒,包括特应性皮炎(Atopic dermatitis,AD)牛皮癣以及多种系统性疾病,是一种复发性、慢性、非传染性的炎症性疾病,其显著特征是皮肤持续剧烈瘙痒达到6周以上乃至终身。临床表现以特应性皮炎为例,包括湿疹样出疹,如红斑、丘疹、特定部位的渗出性病变,皮肤屏障受损,具体取决于患者的年龄(婴儿、儿童和成年)和皮肤干燥程度、遗传因素、环境刺激、表皮屏障缺陷、免疫失调等。几十年来,不仅在城市化和经济程度发展较高的国家,而且在发展中国家,慢性痒范式一直在稳步上升,据统计,仅AD一种的发病率,自20世纪70年代以来,在工业化国家,就增加了2~3倍,全球约有15 %~20 %的儿童和1 %~3 %的成人受到影响。AD对患者的生活质量有显著的影响,由AD患者的家庭和照顾者的负担的直接和间接费用约377亿美元。慢性瘙痒发生在大多数AD患者中,是AD的最主要也是最难以控制的症状,且患病率高达87%~100%。此外,慢性瘙痒和相关的抓挠行为是一个动态的病理过程的组成部分,称为搔抓循环。抓挠行为通过损害皮肤上皮细胞而加剧瘙痒感。上皮细胞应激反应会释放细胞因子、蛋白酶和抗菌肽(Antimicrobial peptide,AMPs),可以激活免疫细胞促进炎症。细胞也可以通过细胞因子和蛋白酶等可溶性介质直接激活瘙痒感觉神经元。神经元释放神经肽也会引起神经源性炎症。与此相反,免疫细胞产生的细胞因子和蛋白酶与感觉神经系统相连,也会介导瘙痒传递。AD的病因复杂,遗传、免疫和环境因素等引起的皮肤屏障功能异常和免疫紊乱,被认为是AD发病机制的关键。AD与免疫功能障碍相关的发病机制包括血清中免疫球蛋白IgE水平升高、对过敏原敏感、T辅助性2(T helper 2,Th2)细胞因子的主导优势、炎症性树突状表皮细胞和朗格汉斯细胞中IgE的受体表达增加和胸腺基质淋巴细胞生成素(Thymic stromal lymphopoietin,TSLP)表达增加。
近年来,关于AD主要是由免疫异常(由内而外理论),还是由表皮屏障功能障碍(由外而内理论)引起的,一直存在着很大的争论。在这些研究中,发现最多的是涉及编码聚丝蛋白(Filaggrin,FLG)基因变异。另外,AD高的遗传风险与皮肤屏障蛋白FLG的突变也有关联。FLG是一种结构蛋白,通过中间丝的聚集建立外表皮屏障,这被认为是建立角质层结构和功能的关键步骤。此外,FLG影响细胞分化,阻遏过敏原渗透,有助于天然保湿因子的合成,这对皮肤的水合作用很重要。最近发现,FLG可以抑制屋尘螨源性的磷脂酶的抗原形成,表明FLG可以直接阻遏过敏原侵入。FLG基因的功能丧失的突变在寻常型鱼鳞病和AD患者中都有描述。FLG功能缺失突变的个体患AD的风险是正常个体的3~5倍,并且这些个体更易患哮喘和花生过敏。AD屏障功能的破坏是多因素的,包括遗传因素,如FLG突变和抓挠造成的物理损伤。除此之外,皮肤屏障功能还可以被微生物生态失调进一步破坏,包括与金黄色葡萄球菌和马拉色酵母菌定殖。Th2型皮肤免疫活动也会导致皮肤屏障基因进一步下调,加重了的皮肤屏障功能的缺陷。
基于目前AD发病率居高不下及其治疗手段的局限性,亟待寻求治疗慢性瘙痒症等疾病新的药用靶点。
公开于该背景技术部分的信息仅用于加深对本公开的背景技术的理解,而不应当被视为承认或以任何形式暗示该信息构成本领域技术人员所公知的现有技术。
发明内容
发明人研究发现,STAT6/IL-4和IL-13信号通路涉及皮肤的屏障功能以及Th2细胞免疫作用,导致瘙痒和炎症的产生。首先通过抑制STAT6(Y641)的磷酸化,能够阻遏Th2细胞的分化,减少IL-13、IL-4和CCL8等瘙痒因子和炎症因子的分泌,破坏瘙痒信号的传递;其次,通过上调角质形成细胞中皮肤屏障基因FLG和IVL的表达,来改善皮肤屏障功能,以降低机体对外源性瘙痒源的敏感度和皮肤的损伤,为治疗慢性瘙痒症等疾病提供了新的药用靶点。
鉴于以上研究发现,本申请提供了一种STAT6作为药物靶点在制备治疗特应性皮炎和慢性瘙痒症的药物中的应用,首次以STAT6为药物靶点,用pSTAT6(Y641)的抑制剂(AS1517499和AS1810722)阻遏瘙痒信号传递、病灶部位免疫细胞的浸润以及皮肤屏障功能的损伤,为慢性瘙痒症等疾病提供了新的治疗方法。具体而言:
以STAT6为作用靶点的制剂在制备抑制瘙痒持续产生、病灶部位免疫细胞的浸润和改善皮肤屏障功能的药物中的应用,包括利用该制剂制备抑制病灶部位免疫细胞浸润的药物,或是利用该制剂制备抑制IL-13、IL-4和CCL8等瘙痒因子和炎症因子转录表达的药物,或是利用该制剂制备改善皮肤屏障功能,并上调皮肤屏障基因FLG和IVL等表达的药物。
在本申请公开的一些实施例中,所述以STAT6为靶点的药物包括:抑制STAT6活性的小分子类抑制剂和拮抗剂(如AS1517499、AS1810722、YM-341619),抑制STAT6磷酸化抑制剂(如AS1517499、AS1810722),竞争性结合STAT6蛋白的嵌合型的多肽或重组蛋白(如STAT6-IP),特异性抑制STAT6表达及转录的抑制剂(如stat6基因的shRNA表达载体),抗STAT6及其磷酸化形态的免疫球蛋白和抗体类抑制剂,特异地结合到STAT6的特异抗体及其片段人源化抗体。
本申请实施例中提供的一个或多个技术方案,至少具有如下技术效果或优点:
首次发现以STAT6为靶点设计的药物可以一方面通过调控其下游信号分子IL-13和IL-4阻遏外周神经至中枢神经的痒觉环路,缓解瘙痒信号的传递和病灶部位的炎症反应;另一方面可以调节皮肤角质形成细胞的屏障功能,上调皮肤屏障相关基因FLG和IVL转录表达,防止皮肤屏障功能的进一步恶化,为特应性皮炎和慢性瘙痒症提供了新的治疗途径。
附图说明
图1为本申请一实施例中小鼠慢性痒AD模型构建和AS 1517499药物效果分析;其中,AD小鼠模型构建和药物处理方法的示意图为(a);AD小鼠模型抓挠次数统计结果为(b)、(c)、(d)、(e)(n=8);抑制剂AS 1517499组和vehicle对照组的AD小鼠的耳厚变化为(f)(n=8);抑制剂AS 1517499组和vehicle对照组小鼠的体重比较为(g)、(h);数据采用Mean ±SEM,ns,P>0.05,*P<0.05,**P<0.01,***P<0.001,student t-test。
图2为本申请一实施例中AS 1810722对慢性痒小鼠搔抓的影响;其中,AD小鼠模型构建和药物处理示意图为(a);AD小鼠模型抓挠次数统计图 (n=8)为(b)、(c)、(d);AD模型小鼠体重变化为(e)、(f);数据采用Mean ± SEM,ns,P>0.05,*P<0.05,**P<0.01,studentt-test。
图3为本申请一实施例中pSTAT 6(Y 641)抑制剂对慢性痒小鼠IL-4、IL-13、CCL8、FLG和IVL基因转录的影响;其中,AS 1517499和vehicle治疗后的AD小鼠左耳IL-13(a)、IL-4(b)、CCL 8(c)、FLG(d)和IVL(e)转录基因的RT-qPCR结果(n=5);AS 1810722和其vehicle处理后的AD小鼠左耳IL-13(f)、IL-4(g)、CCL 8(h)、FLG(i)和IVL(j)转录基因的RT-qPCR结果(n=5);数据采用Mean± SEM,*P<0.05,**P<0.01,student t-test。
具体实施方式
pSTAT6(Y641)作用靶点的选择理论基础及依据:
Th2细胞的分化通过激活信号转导和转录激活因子6(Signal transducer andactivator of transcription 6,STAT 6)通路进行调控,对AD的发生和发展至关重要。许多用于治疗AD的疗法已被应用于改善患者的生活质量,包括光疗、糖皮质激素、全身免疫抑制剂和单克隆抗体Dupilumab,但其效果并不理想,风险隐患仍有待解决,且单克隆抗体药物价格极高,非平民化药物。在AD皮肤病变中,已发现Th 2、Th 1和 Th 17分泌的细胞因子增加,而作为细胞因子介导的信号转导通路STAT 6的激活,可加剧疾病的发展;其中,IL-4在STAT 6的激活中起着重要作用;此外,STAT 6还可以通过调节B细胞分化和促进IgE转换对免疫应答产生显著影响。因此,STAT 6在过敏性疾病中是一种有效的传导因子和激活因子,Th 2免疫应答异常也与STAT 6通路的激活息息相关。它们导致细胞因子、趋化因子和IgE的产生增加,从而加剧AD的炎症反应,然而目前对于特异性抑制STAT 6通路激活治疗慢性痒的药物尚无研究报道。
STAT 6基因编码850个氨基酸,STAT 6蛋白的酪氨酸641(Y 641)磷酸化标志着STAT 6的激活。STAT 6主要参与IL-4和IL-13信号转导,IL-4或IL-13与IL-4受体的结合导致两个受体亚基的二聚化,并导致IL-4受体内的酪氨酸残基被Janus激酶 (Januskinases,JAKs)磷酸化。STAT 6单体与IL-4受体细胞内的磷酸化酪氨酸残基结合,并被JAKs磷酸化。随后,磷酸化STAT 6单体形成同型二聚体,然后转移到细胞核中,在那里它们调节IL-4和IL-13效应基因的表达。此外,STAT 6一旦被激活,会促进Th 2主调控因子GATA结合蛋白3(GATA-bianding protein,GATA 3)的表达,GATA 3负责Th 2效应细胞因子的表达。反过来,GATA 3结合并修饰IL-13和IL-4的基因,导致Th 2相关细胞因子表达增强。IL-4/STAT6信号转导在两个GATA 3启动子的活性中起关键作用,从而控制GATA 3表达的开始和维持。STAT 6不仅参与Th 2分化的起始,还通过诱导趋化因子和其他Th 2相关基因的表达来维持Th 2表型。
除此之外,STAT 6还参与皮肤屏障基因的表达调控。在表皮角质形成细胞中,IL-13/IL-4结合IL-4受体/IL-13受体异源二聚体并激活下游JAK 和STAT 6/STAT 3。IL-13/IL-4-JAK-STAT6/STAT3的激活可抑制芳香族化合物受体(Aryl hydrocarbon receptor,AhR)介导的皮肤屏障基因的上调。同时,AHR的激活抑制IL-13/IL-4介导的STAT 6磷酸化,导致FLG基因的上调。此外,活化的IL-13/IL-4-JAK-STAT 6/STAT 3通路抑制OVOL 1的胞质核转位,进而抑制FLG和LOR的表达。研究表明,IL-13诱导的STAT6激活诱导角质形成细胞产生骨膜蛋白,骨膜蛋白上调IL-24表达,然后IL-24通过激活STAT 3途径抑制FLG的表达。这些结果表明,IL-13/IL-4-STAT 6影响多个信号通路,不仅抑制皮肤屏障功能的蛋白表达,而且还参与Th 2细胞的相关基因的表达等。不仅如此,IL-4处理后的角质形成细胞的细胞膜的屏障功能也被破坏,细胞表面钙粘蛋白的分布被改变。与野生型小鼠相比,STAT 6缺陷的小鼠皮肤屏障功能显著上调,皮肤含水量升高,pH降低,伊文思蓝通透性降低,IVL和FLG表达增加。此外,STAT 6和STAT 3可以协同产生多种促炎的细胞因子(尤其是Th 2细胞因子)引起的皮肤过敏性炎症。
在以下实施例中所涉及的仪器设备如无特别说明,均为常规仪器设备;所涉及的试剂及原料如无特别说明,均来源于常规的商业渠道;所涉及的检测、测试及方法,如无特别说明,均为常规方法。
为了更好的理解本申请技术方案,下面将结合说明书附图以及具体的实施方式对上述技术方案进行详细的说明。
实施例一:以pSTAT6(Y641)为靶点的药物试验验证
本实施例以pSTAT6(Y641)的抑制剂AS1517499治疗慢性痒MC903模型小鼠为例。
1.试剂配置
固体MC903;Tween-80;无水乙醇;聚乙二醇300;二甲基亚砜;生理盐水。
将固体的MC 903溶解于无水乙醇中,使其终浓度为4nmol/20μL,放置于-80℃保存。
将5mg的AS 1517499溶解于160μL的DMSO中,配制高浓度的母液,放于-80℃冰箱中保存。
工作液配制:将母液溶解于10 % DMSO+40 % PEG 300+5 % Tween+45 %盐溶液中。
2.慢性痒模型小鼠的建立和治疗
首先,将16只6~8周的雌性C57BL/6小鼠随机分为两组(8只/每组),并命名为vehicle对照组和抑制剂AS1517499组。然后,用游标卡尺和天平测量小鼠的耳朵厚度以及体重(每天在同一时间对小鼠耳厚、体重和抓挠情况进行统计和分析)。
第1-6天,每天对每组小鼠左耳背部涂抹4nmol/20μL的 MC 903,右耳背部涂抹20μL的无水乙醇;然后用动物行为学成像系统记录小鼠60 min的抓挠行为。
第7-8天,开始对小鼠腹腔注射68μL(10mg/Kg)的AS 1517499进行治疗;vehicle对照组注射等体积的vehicle。一小时后,在小鼠的耳背部涂抹MC903和无水乙醇并进行录像。
第9-10天,增加抑制剂的使用量至15mg/Kg,其余步骤同上。
分组如下:
①10%DMSO+40%PEG300+5%Tween 80+45%盐溶液(MC903+vehicle);
②10%DMSO+40%PEG300+5%Tween 80+45%盐溶液(MC903+AS1517499)。
结果表明(图1),在构建小鼠模型的第7-10天,与vehicle组相比,抑制剂AS1517499组治疗后的小鼠的搔抓行为出现了显著的降低;随后,又根据小鼠每日耳厚的变化统计,发现抑制剂AS1517499组相比于vehicle对照组出现了显著的减少;但两组小鼠的体重并没有出现差异,表明该抑制剂在实验期间并未影响小鼠的体重。
实施例二:以pSTAT6(Y641)为靶点的药物试验验证
本实例以pSTAT6(Y641)的抑制剂AS1810722治疗MC903模型小鼠为例。
1.试剂配置
配制4 nmol/20 μL的MC 903溶液;二甲基亚砜;无水乙醇;生理盐水;
称取2g β-环糊精,然后溶解于8ml的生理盐水中;
将5mg的AS 1810722溶解于166.6μL的DMSO中,配制高浓度的母液,放于-80℃冰箱中保存;
工作液的制备:将母液溶解于5 % DMSO+20 % β-环糊精盐溶液中。
2. AD模型小鼠的建立和治疗:
将16只6-8周的雌性C57BL/6小鼠随机的分为两组,分别为抑制剂AS1810722组和vehicle对照组,并被安置在一个无病原体的和12小时光暗循环的动物房中。用游标卡尺和天平测量小鼠的耳朵厚度以及体重(每天在同一时间记录小鼠耳厚、体重和抓挠情况)。
构建小鼠模型期间,每天使用抑制剂AS1810722的68 μL(5 mg/Kg)对抑制剂AS1810722组小鼠进行灌胃治疗;vehicle对照组喂食等体积的vehicle。一小时后,每组小鼠左耳耳背部涂抹4 nmol /20 μL的 MC 903,右耳耳背部涂抹20 μL的无水乙醇;然后用动物行为学成像系统记录小鼠60 min的抓挠行为,最后对搔抓结果进行统计和分析。分组如下:
①5%DMSO+95%(20 % β-环糊精盐溶液)(MC903+vehicle)
②5%DMSO+95%(20 % β-环糊精盐溶液)+AS1810722(MC903+vehicle)
结果显示(图2),在使用抑制剂的第8、13和14天,与vehicle组相比,抑制剂AS1810722组治疗后的小鼠的搔抓行为出现了显著的下调,但两组小鼠的体重并没有出现差异,表明该抑制剂在实验期间并未影响小鼠的体重。
实例三:以pSTAT6(Y641)为靶点的药物试验验证
以pSTAT6(Y641)抑制剂组和其vehicle对照组模型小鼠左耳组织的RT-qPCR实验为例。
1.小鼠耳组织样本RNA的提取:
取出30 mg的小鼠耳部的皮肤组织样本,放在冷却的研钵和研杵上,然后立即加入液氮进行研磨。使用研钵将组织研磨成粉末(直到组织变成细粉),然后向研钵中加入1.5mL的TRIzol。收集TRIzol(含有组织粉末)到一个无菌无酶的2 mL离心管中,然后用匀浆器涡旋。在室温的条件下孵育5 min。然后,在含有1.5 mL的TRIzol试剂中添加0.3 mL氯仿,室温放置孵育5 min。12000 g,4 ℃离心15 min。溶液分离成红色有机相、中间相和上层无色的水相。用无RNA酶的枪头将水相(含有RNA)转移至新的无菌无酶的离心管中,然后加入0.75 mL异丙醇,在室温条件下孵育12 min左右。在4℃,12000 g的条件下,离心10 min;RNA在离心管的底部形成白色沉淀,弃去上清。向离心管中加入1.5 mL 75 %乙醇重新悬浮RNA沉淀。轻轻地涡旋样品,然后将样品放入4 ℃,7500 g 的离心机中,离心15 min,尽可能的弃去上清。在通风橱中室温放置30 min。用30 μL无RNA酶的水溶解RNA样品,并放在55℃的金属浴中加热10 min左右。然后,测量RNA浓度,并将RNA样品放入-80℃冰箱保存或直接进行反转录实验。
cDNA的合成:
在RNA提取后用Nanodrop测量RNA浓度,并调整其终浓度至1μg/10μL。采用cDNA逆转录试剂盒(Thermo Scientific),方法如表1所示,将RNA转录为cDNA,cDNA合成反应条件如表2所示。
表1 cDNA逆转录反应体系
成分 | 体积(μL) |
10×RT Buffer | 2.0 |
25×dNTP Mix | 0.8 |
10×RT Random buffer | 2.0 |
MultiScribe™ Reverse Transcriptase | 1.0 |
Nuclease-free H<sub>2</sub>O | 4.2 |
Total RNA | 10 |
表2 cDNA合成反应条件
Setting | Step1 | Step2 | Step3 | Step4 |
Temp | 25℃ | 37℃ | 85℃ | 4℃ |
time | 10min | 120 min | 5 min | ∞ |
2. 荧光定量PCR(RT-qPCR)方法:
配置RT-qPCR的10 μL反应体系(每个样品5 mL SYBR+2 μL水+1 μL cDNA+2 μLMix引物),将配置好混匀后的反应体系分别加入PCR板的96孔中,然后进行封膜,并在2000rpm,离心6 min除去气泡。将PCR板放入RT-qPCR仪中进行RT-qPCR反应,分组如下:
①MC903+Vehicle治疗组的cDNA样品(MC903+Vehicle)
②MC903+AS1517499治疗组的cDNA样品(MC903+AS1517499)。
RT-qPCR的反应条件:
第一阶段:50℃ 2min。
第二阶段:95℃ 10min。
第三阶段:40个循环,95℃ 15s,60℃ 1min。
溶解曲线为:95℃ 15s,60℃ 1min,95℃ 15s。
结果显示(图3):通过RT-qPCR的结果分析显示,相比于vehicle对照组,pSTAT 6(Y641)抑制剂AS1517499组治疗的小鼠的左耳中,STAT 6下游的与瘙痒相关的IL-13和IL-4的转录产物显著减少,炎症因子CCL 8的mRNA转录也出现了明显下调。然后,又通过RT-qPCR检测了抑制剂组和vehicle对照组的皮肤屏障相关基因的表达,发现抑制剂组小鼠的皮肤屏障相关基因FLG和LVL的表达明显增加。除此之外,还用RT-qPCR检测了抑制剂AS1810722与其vehicle治疗后的小鼠病灶部位的RNA转录水平,发现抑制剂组中瘙痒因子和炎症因子IL-4,IL-13和CCL8转录水平下调,FLG和IVL的转录增加。
由以上相关试验验证可知,使用STAT6(Y641)磷酸化的特异性抑制剂(腹腔注射AS1517499或口服AS1810722)抑制STAT6(Y641)的磷酸化,可从两个方面来达到治疗作用:
①减少免疫细胞的皮内浸润水平和下调STAT6下游的瘙痒因子IL4,IL13和趋化因子CCL8的基因转录,阻遏病灶部位的炎症反应和瘙痒信号的产生;
②上调皮肤角质形成细胞中屏障基因FLG和IVL的表达,改善皮肤屏障功能,提高机体对外源性过敏原和刺激物的阻遏作用,起到抑制慢性瘙痒的恶化和皮肤损伤的作用,为慢性瘙痒症的治疗提供了新的方法和思路。
尽管已描述了本发明的一些优选实施例,但本领域内的技术人员一旦得知了基本创造性概念,则可对这些实施例做出另外的变更和修改。所以,所附权利要求意欲解释为包括优选实施例以及落入本发明范围的所有变更和修改。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本申请权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (9)
1.作用于STAT 6靶点的物质成分在制备治疗慢性瘙痒症的药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述物质成分为抑制STAT6活性的拮抗剂或小分子类抑制剂,或为抑制STAT6磷酸化的抑制剂,或为竞争性结合STAT6蛋白的嵌合型的多肽或重组蛋白,或为抗STAT6及其磷酸化形态的免疫球蛋白或抗体类抑制剂。
3.根据权利要求1所述的应用,其特征在于,所述物质成分为AS1517499、AS1810722、YM-341619及其衍生物、STAT6-IP、stat6基因的shRNA表达载体中的至少一种。
4.抑制STAT6活性的拮抗剂或小分子类抑制剂在制备抑制瘙痒因子IL-4、IL-13和趋化因子CCL8基因转录的药物中的应用。
5.抑制STAT6活性的拮抗剂或小分子类抑制剂在制备上调皮肤屏障相关基因中FLG和IVL基因表达的药物中的应用。
6.抑制 STAT6酪氨酸641磷酸化抑制剂在制备阻遏瘙痒因子IL-4和IL-13表达的药物中的应用。
7.竞争性结合STAT6蛋白的嵌合型多肽或重组蛋白在制备抑制瘙痒因子IL4、IL13和趋化因子CCL8转录及阻断角质细胞中IL-13/STAT6/periostin通路的药物中的应用。
8.特异性抑制STAT6表达及转录的抑制剂在制备抑制IL-4和IL-13激活STAT6信号通路中的应用。
9.抗STAT6及其磷酸化形态的免疫球蛋白或抗体类抑制剂在制备降低和阻断STAT6水平和其磷酸化水平的药物中的应用。
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