CN103045584A - 一种新的研究肠道免疫稳态的动物模型 - Google Patents
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Abstract
本发明涉及获得平滑肌特异性剔除PTEN基因产生小鼠模型及该小鼠自发产生肠道淋巴细胞活化并模拟人类结肠淋巴结节增生病理表现两个方面的应用，属于生物技术领域。该方法包括如下步骤：通过交配获得平滑肌细胞特异性剔除PTEN基因的突变小鼠，该小鼠产生突变表型之后对其进行检测和鉴定，通过组织学手段确定其淋巴结节增生的具体细胞构成，并找到一定的分子基础，得出PTEN基因在平滑肌细胞中剔除可导致结肠免疫紊乱，炎性细胞浸润，粘膜渗透性增加等病理表现，这一过程可能是通过调控MCP-1基因来完成的这一结论。该小鼠模型可用于进一步研究平滑肌细胞在结肠免疫中的作用以及对免疫抑制药物的筛选。
Description
技术领域
本发明通过基因条件剔除技术建立一种新的研究肠道免疫稳态的动物模型，属于生物技术领域。
背景技术
人类的肠道是一个重要的免疫器官，包含多种免疫相关细胞，在维持全身免疫稳态中发挥重要作用。消化道在日常生活中受到外界免疫原的持续刺激，以及各种共生菌的抗原刺激，但能通过特定的机制维持一种免疫抑制的状态，从而形成一个特别的免疫耐受的微环境，称为肠道的免疫稳态。肠道上皮层不仅形成一个阻碍病原侵入的物理屏障，同时也包含特异的天然及获得性免疫系统。保持免疫的非活化状态，需要对肠道内免疫细胞和上皮渗透性的正确调控。特定的淋巴结构，如小肠中派伊尔氏结和结肠中分立淋巴结节等，对肠腔中抗原进行筛选和分析，从而调节上皮中M细胞的分泌功能最终调节免疫能力。
肠道免疫疾病是一个综合的多种发病机制导致的疾病，对肠道免疫的扰乱可导致各种形式的免疫疾病，如溃疡性结肠炎，克罗恩氏病，炎性小肠炎等，并且与结肠癌的早期分化有较高的相关性。确定的原因始终是不明了的，肠上皮的渗透性增加可能具有一定的作用。同时，肠道内淋巴小节增生也是一种较为罕见的肠道免疫紊乱形式，表现为粘膜层及粘膜下层的大量的淋巴细胞浸润，形成坚实的淋巴增生聚集，包含不同大小的生发中心，以B细胞为主要细胞类型。肠道淋巴结节增生的病理原因也并不明确，可能与细菌的持续感染有关。
最近其它类型的细胞也被证明可参与调节肠道免疫，如基质细胞对于T细胞肠道归巢具有重要的调节作用，结肠肌成纤维细胞也具有抗原呈递功能，这些发现提示肠道免疫的调节是一个多种细胞参与的复杂生物过程。平滑肌是普遍存在于全身多种组织中的细胞类型，对消化道、膀胱、血管等组织具有维持形态、收缩蠕动等物理功能，同时在生理及病理条件下也具有重要的分泌能力，可参与调节炎症、动脉硬化等病理过程，是细胞因子、血小板因子等多种因子的不可或缺的来源。肠道平滑肌对肠道免疫的调控作用的了解并不充分，因此更多的深入研究是十分必要的。
PTEN是一个脂酶、蛋白酶双功能酶，通过直接调节PIP3并负调控PI3k/Akt/mTOR信号通路，调节细胞的增殖和凋亡，从而达到其重要的抑癌功能。在肠道免疫调节的研究中，大部分都集中在对肠淋巴细胞和上皮细胞的功能上，对平滑肌的关注相对较少，而我们在平滑肌细胞中特异性剔除PTEN后发现该小鼠自发产生肠道淋巴结节增生及全身免疫活化的表型，说明平滑肌也是重要的参与调节肠道免疫的细胞类型，同时PTEN对调节肠道免疫的信号通路也具有直接而必需的调控作用。通过对下游基因的研究，我们推测PTEN下游重要的调节肠道免疫的因子是单核细胞趋化蛋白-1(MCP-1)，PTEN缺失的平滑肌细胞中MCP-1的表达量增加，从而导致T淋巴细胞活化增生。该小鼠模型不仅一定程度上揭示了平滑肌调节肠道免疫的作用机制，更成功地模拟了人类中结肠淋巴小结增生的病理现象，是稳定可靠的动物模型，可用于对免疫抑制类药物功能的研究。
发明内容
本发明的目的是提供人类肠淋巴细胞小结增生的可能机制机理，对病理研究提供分子基础。本发明的另一个目的是提供一种稳定可靠的小鼠模型，成功模拟人类病理过程。
本发明的有益效果：本发明利用基因剔除技术，发现平滑肌细胞在肠道免疫稳态的调节中具有重要作用，得到模拟人类病理过程的工具小鼠，可用于不同类型的免疫抑制类药物研究，开拓了病理分析和药物筛选的道路。
附图说明
图1为小鼠平滑肌细胞特异剔除PTEN基因的基因型鉴定结果。
图2为PTEN基因剔除后肠道淋巴结节增生过程。
图3为PTEN基因剔除后淋巴结节内淋巴细胞的具体构成类型。
图4为PTEN基因剔除后肠道炎性细胞浸润增加，肠上皮细胞渗透性增加
图5为PTEN基因剔除后分子水平的具体变化。
具体实施方式
小鼠的饲养和繁育：PTEN条件锚定小鼠及a-SMA-Cre转基因小鼠由中国军事医学科学院杨晓研究员惠赠。
C57BL/6J购自Jackson实验室(美国)，饲养在AAALAC认证的SPF级的动物房里，动物房位于南京大学模式动物研究所。所有的小鼠操作均严格按照“Principles of laboratoryanimal care”(美国国立卫生院发行号85-23，1985修订版；
http://grantsl.nih.gov/grants/olaw/references/phspol.htm)和“the care and use oflaboratory animals”(美国国家研究理事会，1996).并得到了模式动物研究所动物管理委员会的批准和监督。
实施例一
我们通过多聚链式扩增反应(PCR)技术对条件剔除小鼠进行基因型鉴定，在平滑肌细胞裂解提取得到的基因组DNA中特异地扩增出PTEN剔除后条带，所使用的PCR引物序列为：PTENdeleted：5’-ACTATTGAACAGAATCAACCC-3’，5’-GTCACCAGGATGCTTCTGAC-3’；。同时对小鼠鼠尾基因组DNA进行PCR鉴定以确定基因型，使用扩增引物为：PTEN flox：5’-ACTCCCACCAATGAACAAAC-3’，5’-CTCCTCTACTCCATTCTTCCC-3’；a-SMA-Cre：5’-AGCCTGTGACACTCCCGCTCTT-3’，5’-ACGCCTGGCGATCCCTGAAC-3’。使用该方法可得到纯合条件剔除，杂合条件剔除及野生型小鼠。使用纯合条件剔除和野生型小鼠作为实验组和对照组。
实施例二
小鼠结肠组织的组织学研究。分别取1月龄，2月龄和5月龄的小鼠，用4％多聚甲醛固定从肛门向上的约2cm结肠组织，进行大体形态学分析，然后石蜡包埋切片，进行HE染色。对直接冰冻包埋的结肠组织进行冰冻切片，然后用不同抗体进行免疫荧光研究。结果显示肠道增生的淋巴结节主要组成细胞类型为B细胞，周围由少量T细胞及单核细胞围绕，同时含有不止一个增大的生发中心。其中CD3，B220，CD11c抗体购自eBioscience公司，PNA购自Sigma-Aldrich公司。
实施例三
使用QPCR技术对结肠全组织及分离的结肠粘膜肌层进行分子水平的分析。将每个基因型的1个月大的小鼠各6只断颈处死，取肛门向上的约2cm结肠组织，在磷酸盐缓冲液(PBS)中洗去食物残渣，置于RNA iso中匀浆，提取RNA，将各1ug RNA反转成cDNA，然后real-timePCR反应，结果见图5.分离结肠粘膜肌层(含有粘膜下小动脉)步骤为，将洗净的结肠组织在PBS中用手术刀片小心地刮去平滑肌层，然后在5mM EDTA/HBSS中于37摄氏度水浴振荡消化，共3次每次30分钟，将上皮组织消化除去，剩下的为粘膜肌层，提取RNA及real-timePCR过程与全结肠相同。反转录使用TAKARA单链反转试剂盒，使用ABI7300进行real-time PCR反应。使用的引物序列均为5’向3’：
MCP-1 GGTGTCCCAAAGAAGCTGTA
ACGGGTCAACTTCACATTCA
SDF-1a TCCAAACTGTGCCCTTCA
GGCGGAGTGTCTTTATGC
MMP-9 ATCATAGAGGAAGCCCATTACA
GGGCCTAGACCCAACTTATC
Il-1a AGCTTCAGGCAGGCAGTA
CATCCCATGAGTCACAGAG
除上述实施例外，本发明还可以有其他实施方式。凡采用等同替换或等效变换形成的技术方案，均落在本发明要求的保护范围。
Claims (5)
1.一种基于基因重组技术产生PTEN在平滑肌内特异性剔除研究小鼠肠道免疫稳态的方法，包括如下步骤：
步骤一、通过转基因技术产生平滑肌细胞特异性的Cre转基因工具鼠，在平滑肌特异性基因a-SMA的启动子后接入Cre重组酶序列，并通过原核注射产生过表达的转基因小鼠，可以介导条件锚定小鼠在平滑肌细胞中产生特异性的条件剔除。
步骤二、通过交配手段获得平滑肌细胞特异剔除PTEN基因的条件剔除小鼠。
2.基于权利要求1所述的基于基因重组技术产生PTEN在平滑肌内特异性剔除研究小鼠肠道免疫稳态的方法，其特征在于：该小鼠表现出早期发生的肠道免疫激活表型，并导致全身免疫活化反应。
3.基于权利要求1所述的基于基因重组技术产生PTEN在平滑肌内特异性剔除研究小鼠肠道免疫稳态的方法，其特征在于：所述小鼠的基因型包括纯合剔除，杂合剔除与野生型。
4.基于权利要求1和2所述的基于基因重组技术产生PTEN在平滑肌内特异性剔除研究小鼠肠道免疫稳态的方法，在研究人类肠道免疫紊乱中的应用。
5.基于权利要求1和2所述的基于基因重组技术产生PTEN在平滑肌内特异性剔除研究小鼠肠道免疫稳态的方法，在筛选针对肠道免疫紊乱中靶向药物的作用。
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| CN103609519A (zh) * | 2013-11-12 | 2014-03-05 | 邓飞 | Balb/c小鼠间变性大细胞淋巴瘤动物模型的构建方法 |
| CN103609519B (zh) * | 2013-11-12 | 2015-09-09 | 邓飞 | Balb/c小鼠间变性大细胞淋巴瘤动物模型的构建方法 |
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