CN113444184A - 一种环瓜氨酸蛋白短肽及其应用 - Google Patents
一种环瓜氨酸蛋白短肽及其应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域，涉及一种环瓜氨酸蛋白短肽及其应用。该环瓜氨酸蛋白短肽的制备方法包括如下步骤：S1.选取瓜氨酸波形蛋白短肽26‑44位氨基酸序列：SSXSYVTTSTXTYSLGSAL；S2.将上述短肽中第1、14位的精氨酸替换为半胱氨酸，形成二硫键，合成环状短肽：
Description
技术领域
本发明属于生物医药技术领域，涉及一种环瓜氨酸蛋白短肽及其应用。
背景技术
类风湿关节炎(Rheumatoid arthritis,RA)是一种最常见的以侵蚀性关节炎为特点的慢性全身性自身免疫病；其重要病理特征慢性滑膜炎、滑膜血管翳的形成常引起受累关节出现进行性破坏，导致很高的致残率。近些年来，大量基础与临床研究揭示瓜氨酸化蛋白及其特异性抗体在RA免疫炎症反应的启动和维持过程中发挥重要作用，瓜氨酸蛋白作为RA发病可能的始动抗原而受到广泛关注。然而，瓜氨酸蛋白是在何时何处怎样打破免疫耐受触发免疫反应等问题仍未完全明确。以瓜氨酸蛋白诱导建立起来的一些类风湿关节炎鼠模型在关节炎发生部位与病理特点上，尚与人类RA发病存在较大差异；且由于啮齿类鼠模型关节结构太小，限制了X线、关节超声检查对模型关节炎监测的运用。因此，研发以高纯度瓜氨酸蛋白短肽诱导性猕猴RA模型，进行影像学和病理对应研究，不仅对探讨瓜氨酸化蛋白在RA发病机制中确切作用而且对影像检查在RA诊断和预测中具有重要意义。
人类疾病动物模型研究是深入探讨人类疾病发生发展机制的最有效途径之一。人类借助对疾病动物模型的认识，能更有效地阐明人类疾病的发病机制及其发展规律，在防治疾病、推动医药卫生发展上发挥重要作用。近半个多世纪以来，国内外使用大鼠、小鼠、兔、鸡、猴等进行了大量的RA动物模型研究，并成功建立了一些比较成熟的动物模型，目前应用较广泛的且较成熟的整体动物实验模型有三类：一是免疫介导性的诱导性关节炎模型，如佐剂性关节炎、CIA、四甲基+五烷诱导的关节炎、多聚糖蛋白诱导的关节炎，链球菌细胞壁诱导性关节炎等；二是转基因自发性关节炎模型；三是免疫缺陷鼠-人类风湿关节炎异种移植模型等。
总的来说，诱导性关节炎模型在部分表现和免疫介导炎症反应的发病机制上可以模拟人类RA，特别是CIA已经成为中西医药理药效及病理机制研究应用最多的模型。但是，这些RA模型多为自限性，缺乏人类RA慢性侵蚀性特点，其血清中很少检测到RF、抗CCP等RA特异性抗体；而且同一种模型由于诱导剂乳化方法、注射剂量、注射部位的不同也可表现出不尽相同的关节炎表现。再者，佐剂、胶原蛋白等并不是人类RA的真正启动抗原，其发病机制与人类RA仍有较大差距。因此，上述RA动物模型并不能完全反映人类RA在关节炎表现、免疫学、病理学等方面的特点，更无法阐明人类RA免疫炎症反应的启动和维持过程中的机制，制约RA发病机制研究的进一步发展。而目前的研究认为瓜氨酸蛋白能充当启动RA免疫炎症反应的靶抗原，抗瓜氨酸免疫反应能诱导关节炎；产生的ACPAs能直接或间接介导软骨侵蚀、骨质破坏，在RA的炎症反应和软骨侵蚀、骨质破坏过程中发挥关键作用。
综上所述，优化造模方法，从动物模型的关节炎表现、关节滑膜炎症、病理学特征、多种炎症因子、针对瓜氨酸化蛋白抗原的特异性体液和细胞免疫应答、关节滑膜的瓜氨酸蛋白抗原表达等多途径对该模型进行评价。以人工合成的瓜氨酸化蛋白短肽替代同源蛋白为抗原诱导剂的RA动物模型是非常有意义的选择。
发明内容
本发明的目的在于提供一种环瓜氨酸蛋白短肽及其应用。
本发明的目的可以通过以下技术方案实现：
一种环瓜氨酸蛋白短肽，该环瓜氨酸蛋白短肽的制备方法包括如下步骤：
S1.选取瓜氨酸波形蛋白短肽26-44位氨基酸序列：SSXSYVTTSTXTYSLGSAL；
S2.将上述短肽中第1、14位的精氨酸替换为半胱氨酸，形成二硫键，合成环状短肽：
S3.再将上述环状短肽与血蓝蛋白偶联形成偶联物，即得到环瓜氨酸蛋白短肽。
如上所述的一种环瓜氨酸蛋白短肽在诱导食蟹猴类风湿关节炎中的应用。
本发明的有益效果：
本发明的环瓜氨酸蛋白短肽，由瓜氨酸波形蛋白短肽经替换形成环瓜氨酸化波形蛋白短肽，再配合血蓝蛋白偶联形成；将该环瓜氨酸蛋白短肽应用在诱导食蟹猴类风湿关节炎中，通过对食蟹猴进行二次免疫造模，能够构建符合临床发病特点的大型灵长类动物RA模型，对于RA的药物开发、发病机制探讨，具有重要意义。
具体实施方式
下面将结合实施例对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。
实施例：
一种环瓜氨酸蛋白短肽，该环瓜氨酸蛋白短肽的制备方法包括如下步骤：
S1.选取瓜氨酸波形蛋白短肽26-44位氨基酸序列(Cit-Vim26-44)：SSXSYVTTSTXTYSLGSAL；
S2.将上述短肽中第1、14位的精氨酸替换为半胱氨酸，形成二硫键，合成环状短肽(CCit-Vim26-44)：
S3.再将上述环状短肽与血蓝蛋白(KLH)偶联形成偶联物(CCit-Vim26-44-KLH)，即得到环瓜氨酸蛋白短肽，纯度达98.482％；
一种环瓜氨酸蛋白短肽在诱导食蟹猴类风湿关节炎中的应用，即环瓜氨酸蛋白短肽诱导食蟹猴类风湿关节炎模型的建立，包括如下步骤：
(1)抗原乳化液的制备：将CCit-Vim26-44-KLH加入到乙酸溶液中，一边加入一边使用电动匀浆器进行充分混匀，反复多次，直至形成油包水的白色乳液状，滴至水中不扩散；
(2)造模：造模分为首次诱导免疫和强化诱导免疫两个阶段。首次诱导免疫选择在食蟹猴背部，注射抗原乳化液，分为10个部位皮下注射；强化诱导免疫于首次诱导免疫后每4周进行一次，部位及注射方式同首次诱导免疫相同，共强化诱导免疫2次。
模型评估：
(1)观察免疫诱导前后每周称重记录体重变化及观察有无脱毛等情况。每周采用兽用红外线体表温度计测量猕猴关节温度变化，观察关节局部是否发热，并拍照存档。受累关节活动功能情况：每周观察受累关节的活动情况，注意是否出现关节变形、僵直。观察免疫后每天，食蟹猴是否存在异常行为(目光闪躲、神情冷漠、厌食)或者疼痛反应(行动迟缓、四肢伸展不利)。
(2)血清特异性抗体及炎症细胞因子检测：通过收集食蟹猴外周血，采用魏氏法检测ESR；检测抗CⅡ抗体、抗CCP抗体等自身抗体及检测TNF-α、IL-6等炎症细胞因子的表达情况；血清抗CCit-Vim短肽抗体OD值。
(3)影像学检查：首次免疫后第28、56天，将食蟹猴麻醉后，对其进行影像学检查(关节X线、关节彩超、关节MRI)，并采用相应半定量评分对其关节炎程度进行评定。
(4)组织病理学检测：首次免疫后12周采用安乐死食蟹猴，获取足掌指间关节、腕关节、双膝关节，包埋，切片，HE染色、封片，光镜下观察炎性细胞浸润、滑膜厚度、软骨及骨侵蚀情况。
将本发明的环瓜氨酸蛋白短肽应用在诱导食蟹猴类风湿关节炎中，通过对食蟹猴进行二次免疫造模，能够构建符合临床发病特点的大型灵长类动物RA模型，对于RA的药物开发、发病机制探讨，具有重要意义。
以上内容仅仅是对本发明结构所作的举例和说明，所属本技术领域的技术人员对所描述的具体实施例做各种各样的修改或补充或采用类似的方式替代，只要不偏离发明的结构或者超越本权利要求书所定义的范围，均应属于本发明的保护范围。
Claims (2)
1.一种环瓜氨酸蛋白短肽，其特征在于，该环瓜氨酸蛋白短肽的制备方法包括如下步骤：
S1.选取瓜氨酸波形蛋白短肽26-44位氨基酸序列：SSXSYVTTSTXTYSLGSAL；
S2.将上述短肽中第1、14位的精氨酸替换为半胱氨酸，形成二硫键，合成环状短肽：
S3.再将上述环状短肽与血蓝蛋白偶联形成偶联物，即得到环瓜氨酸蛋白短肽。
2.根据权利要求1所述的一种环瓜氨酸蛋白短肽在诱导食蟹猴类风湿关节炎中的应用。
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