CN114931665A - 六型胶原α2亚基在神经修复产品中的应用 - Google Patents
六型胶原α2亚基在神经修复产品中的应用 Download PDFInfo
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Abstract
本发明提供六型胶原蛋白α2亚基在神经修复产品中的应用,提高了再生神经的有序性,使再生神经纤维在形态学上更加接近正常神经束结构,减少神经与靶器官的错配的概率,提高了神经修复效果;与六型胶原蛋白的使用区别除了更好的促有序性外,还在于,通过基因工程制备了COL6α2亚基蛋白,降低了生产成本,使商业应用具有更大的可能以及能够惠及更多的患者;此外,通过添加有效量的COL6α2亚基蛋白可以制备包括药物、神经移植物、水凝胶等在内的神经修复产品,并提供了制备方法。
Description
技术领域
本发明涉及医药技术领域,具体涉及六型胶原蛋白α2亚基(COL6 α2)在制备促轴突有序化水凝胶中的应用。
背景技术
周围神经损伤是一种常见的致残性疾病。包括端-端神经缝合、自体神经移植、电刺激和组织工程在内的多种方法已被证明能够有效促进周围神经的再生数量和再生速度[1-3]。然而,再生神经纤维的紊乱无序仍然是制约周围神经损伤后功能恢复的重要因素[4-6]。
为增加再生轴突的有序性,目前常用的手段是在神经移植中引入外源性引导信号[7,8]。这类外源性引导信号须满足特定的空间分布模式(如浓度梯度分布的生化导向分子或平行排列的物理引导结构)才能发挥预期的作用[9-11]。由于周围神经组织直径较小但结构精细,因此在神经移植物中构建精细引导信号的技术难度较大。
一种不依赖引导信号的轴突自组织现象为神经有序再生提供了新的途径。有研究报道在周围神经ECM微环境中再生的轴突会自发形成有序的神经束结构[12]。进一步研究发现周围神经ECM中的六型胶原蛋白(COL6)是引发轴突自组织有序化的主要功能分子。 相关实验结果显示,只需在匀质水凝胶中加入适当浓度的COL6,再生轴突即可自发形成有序的神经束结构,这种有序的神经束结构能够降低再生神经与远端靶器官的错配率从而促进神经功能恢复[13]。
上述研究提示COL6能够有效促进再生轴突的有序性,且实施方法简单。但实际应用中也存在两大缺陷。第一,COL6是一种由COL6 α1, COL6 α2 和 COL6 α3组成的蛋白复合物,其生物组装过程相当复杂且分子量巨大(≈2000 kDa)[14],以现有的基因工程或蛋白合成技术均无法实现批量化生产;第二,COL6表现出较其他胶原蛋白更强的免疫原性[15,16], 这也进一步限制了利用异种或同种异体COL6纯化蛋白修复人体神经的可行性。
总体而言,完整的大分子蛋白由于易发生降解变性、抗原性较强、生产成本较高等原因,通常难以成为合适的候选药物。
发明内容
为促进神经再生的自组织有序化,同时解决COL6免疫原性较高,制备难度较大的问题,本发明人通过实验研究发现能够促轴突有序化的COL6主要功能亚基COL6 α2,并通过基因工程手段制备了COL6α2亚基,并且将其应用在水凝胶载体中赋予了常规水凝胶材料促轴突有序化的新功能。
本发明提供六型胶原蛋白α2亚基在神经修复产品中的应用,所述的六型胶原蛋白α2亚基的有效浓度范围为2-100μg/ml。
进一步地,所述的神经修复产品包括:神经移植物、水凝胶。
进一步地,所述的COL6α2亚基为人源性COL6α2亚基。
进一步地,所述的六型胶原蛋白α2亚基蛋白的制备方法包括:
1)扩增:将带有Myc-DDK标签的人源性COL6 α2 ORF克隆质粒转化DH5α大肠杆菌进行扩增;
2)转导:将扩增后的质粒转导HEK293细胞使其表达带Myc-DDK标签的COL6 α2蛋白链;
3)裂解:转导72小时后,收集细胞并用含150 mM NaCl、50 mM Tris-HCL、1%TritonX-100和5mM EDTA的裂解液进行裂解;
4)洗脱:利用Myc亲和凝胶分离带Myc-DDK标记的COL6α2蛋白链,然后用0.15m甘氨酸-盐酸缓冲液(pH 3.0)进行洗脱;
5)透析:利用去离子水对COL6α2洗脱液进行透析;
6)冷冻干燥:对步骤5)进行冷冻干燥,收集COL6α2冻干粉末,即为六型胶原蛋白α2亚基蛋白。
进一步地,所述的水凝胶的制备方法为:将COL6α2纯化蛋白冻干粉末溶于生理盐水中,配成浓度为1 mg/ml的原溶液;将装有COL6α2纯化蛋白的原溶液的容器置于冰盒上,与浓度为10 mg/mL的Matrigel原溶液按1:49的比例混合形成水凝胶;将水凝胶在室温放置5分钟自然凝固。
进一步地,所述的水凝胶的制备方法为:将20μg/mL的COL6α2纯化蛋白溶液与6.9mg/mL的巯基化透明质酸混合,在混合体系中加入1.8mg/mL的聚乙二醇(二醇)二丙烯酸酯交联反应15分钟凝固成胶。
进一步地,所述的神经移植物的制备方法包括:模具成型、定向冻干、凝胶灌注、溶液浸泡。
本发明的有益效果在于:
1)通过在水凝胶中加入COL6α2功能蛋白使得水凝胶材料具备促轴突自组织有序化的作用;
2)COL6α2亚基克服了COL6无法通过基因工程手段制备的不足,且免疫原性较COL6低。附图说明:
图1 为COL6α2结构域(A)和重组COL6α2蛋白(B)结构示意图;
图2 为蛋白银染法显示重组COL6α2的蛋白的纯度;
图3 为不同浓度COL6α2水凝胶体外促进轴突集束及有序化效果图;
图4 为负载COL6α2的水凝胶体外促进轴突集束及有序化免疫荧光效果图;
图5 为负载COL6α2的水凝胶修复大鼠坐骨神经缺损免疫荧光效果图;
图6 为皮下注射等量COL6α2和COL6对血清IgM浓度的影响。
具体实施方式
在六型胶原蛋白用于提高再生神经有序性的研究基础上,为解决六型胶原蛋白免疫原性高、制备难度大,不适合商业推广应用的问题。继续深入对六型胶原蛋白的研究,发现COL6α2 亚基蛋白具有良好的促轴突有序化功能,并且通过基因工程手段可以实现商业制备;此外,探讨了COL6α2亚基蛋白在神经修复产品中的应用,并制备了具有促轴突有序化再生功能的神经修复产品。具体实施方式如下:
实施例一:COL6α2亚基蛋白的制备
1)扩增:自主构建或将商品化的,带有Myc-DDK标签的人源性COL6 α2 ORF克隆质粒(货号 RC209476,OriGene)转化DH5α大肠杆菌进行扩增;
2)转导:将扩增后的质粒转导HEK293细胞使其表达带Myc-DDK标签的COL6 α2蛋白链;
3)裂解:转导72小时后,收集细胞并用含150 mM NaCl、50 mM Tris-HCL、1%TritonX-100和5 mM EDTA的裂解液进行裂解;
4)洗脱:利用Myc亲和凝胶分离带Myc-DDK标记的COL6 α2蛋白链,然后用0.15m甘氨酸-盐酸缓冲液(pH 3.0)进行洗脱,其中,通过蛋白银染技术检测洗脱液中的COL6 α2纯度(图2)
5)透析:利用去离子水对COL6 α2洗脱液进行透析;
6)冷冻干燥:对步骤5)进行冷冻干燥,收集COL6 α2冻干粉末保存于无菌密封干燥的环境。
需要说明的是,从应用角度,也可直接购买商品化的重组人源性COL6α2纯化蛋白,如OriGene公司,货号为TP309476的产品。
实施例二:通过非共价结合方式制备含有COL6 α2的水凝胶产品
将实施例一获得的COL6α2纯化蛋白冻干粉末溶于生理盐水中,配成浓度为1 mg/ml的原溶液,然后与浓度为10 mg/mL的Matrigel原溶液按1:49的比例混合。此时混合水凝胶中COL6 α2的浓度可20μg/mL;混合水凝胶在室温放置5分钟左右即可自3然凝固成胶,此时COL6 α2分子与Matrigel水凝胶分子以非共价结合的方式相互结合。为了保持水凝胶的流动性,整个操作过程应在冰盒上进行。
实施例三:通过化学交联方式制备含有COL6 α2的水凝胶产品
将实施例一获得的COL6 α2纯化蛋白冻干粉末配成溶液后与其他载体水凝胶材料混合,本实施例中选用的是巯基化透明质酸,然后在混合体系中加入聚乙二醇(二醇)二丙烯酸酯(PEGDA)引发COL6α2与巯基化透明质酸分子之间的巯基交联反应,其中,混合体系中COL6 α2的浓度为20 μg/mL,巯基化透明质酸浓度6.9 mg/mL;PEGDA浓度为1.8mg/mL,此反应在室温下15分钟即可形成固态水凝胶。
实施例四:
本实施例与实施例二的区别在于,混合水凝胶中不含有COL6α2。
实施例五:
本实施例与实施例二的区别在于,混合水凝胶中的COL6α2的浓度为2μg/mL。
实施例六:
本实施例与实施例二的区别在于,混合水凝胶中的COL6α2的浓度为100μg/mL。
实施例二、四、五、六的实验结果如图3所示,COL6α2的浓度在2-100μg/mL都有促轴突的作用,但从成本以及综合效果考虑还是优先选择20μg/mL的浓度。
实施例七:富含COL6 α2的神经移植物的制备。
神经移植物可通过溶液浸泡或凝胶灌注的方式将有效浓度的COL6α2负载于多通道导管的材料间隙或孔道中,使常规神经移植物也具备促神经自组织有序化的作用。
实施例八:含COL6α2水凝胶促进再生神经纤维集束及有序化的体外实验
将实施例二获得的预凝胶溶液按2 μg/cm2涂布细胞培养皿底面,吸取多余液体后室温放置5-10分钟成胶,随后将大鼠背根神经节(DRG)组织块种植在包被有水凝胶的培养皿中。在37 ℃培养箱中培养3天后可见有序神经束结构的形成。对照组采用未添加COL6 α2的水凝胶铺板,可见DRG轴突呈现散乱无序的结构(图4)。
实施例九:COL6α2水凝胶修复大鼠坐骨神经损伤
将实施例二获得的富含COL6α2的水凝胶溶液通过注射器注入内径为1mm,长8mm的医用硅胶管,在37℃培养箱中放置10min,待其完全成胶后,将导管放入无菌生理盐水中保存。常规麻醉成年SD大鼠,暴露坐骨神经,切除8mm神经缺损,用负载水凝胶的神经导管桥接神经断端,分层缝合肌肉和皮肤,手术过程全程无菌操作。术后常规饲养,4周后灌注取材坐骨神经,切片染色观察。如图5所示,添加了COL6α2的水凝胶能够显著增加再生轴突的有序性。
实施例十:COL6α2水凝胶免疫原性检测
将成年SD大鼠(两月龄)背部皮肤剃毛后消毒。采集尾静脉血作为免疫前0天组的样本,随后皮下注射0.1mL浓度为100μg/mL的COL6α2蛋白溶液,对照组注射等量的COL6蛋白溶液。于注射后的第3天和第7天分别采集尾静脉血,所有的血液在室温下静置2小时,待其凝固后离心收集血清,通过酶联免疫吸附法(ELISA)检测不同时间点血清IgM的浓度变化。结果显示COL6皮下注射会引起血液中IgM的升高,而等量COL6α2未造成IgM的升高(图6)。
以上实施例仅用以说明本发明的技术方案而非对其限制,尽管参照上述实施例对本发明进行了详细的说明,所属领域的普通技术人员依然可以对本发明的具体实施方式进行修改或者等同替换,而这些未脱离本发明精神和范围的任何修改或者等同替换,其均在申请待批的本发明的权利要求保护范之内。
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SEQUENCE LISTING
<110> 广州医科大学
<120> 六型胶原α2亚基在神经修复产品中的应用
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Val Arg Ser Pro Arg Gly Gly Ala Arg Arg His Ala Glu Leu Ser Phe
930 935 940
Val Phe Leu Thr Asp Gly Val Thr Gly Asn Asp Ser Leu His Glu Ser
945 950 955 960
Ala His Ser Met Arg Lys Gln Asn Val Val Pro Thr Val Leu Ala Leu
965 970 975
Gly Ser Asp Val Asp Met Asp Val Leu Thr Thr Leu Ser Leu Gly Asp
980 985 990
Arg Ala Ala Val Phe His Glu Lys Asp Tyr Asp Ser Leu Ala Gln Pro
995 1000 1005
Gly Phe Phe Asp Arg Phe Ile Arg Trp Ile Cys
1010 1015
Claims (7)
1.六型胶原蛋白α2亚基在神经修复产品中的应用,所述的六型胶原蛋白α2亚基的添加量为2-100μg/ml。
2.根据权利要求1所述的六型胶原蛋白α2亚基在神经修复产品中的应用,其特征在于,所述的神经修复产品包括:神经移植物、水凝胶。
3.根据权利要求1所述的六型胶原蛋白α2亚基在神经修复产品中的应用,其特征在于,所述的COL6α2亚基为人源性COL6α2亚基。
4.根据权利要求1所述的六型胶原蛋白α2亚基在神经修复产品中的应用,其特征在于,所述的六型胶原蛋白α2亚基蛋白的制备方法包括:
1)扩增:将带有Myc-DDK标签的人源性COL6α2ORF克隆质粒转化DH5α大肠杆菌进行扩增;
2)转导:将扩增后的质粒转导HEK293细胞使其表达带Myc-DDK标签的COL6α2蛋白链;
3)裂解:转导72小时后,收集细胞并用含150 mM NaCl、50 mM Tris-HCL、1%Triton X-100和5mM EDTA的裂解液进行裂解;
4)洗脱:利用Myc亲和凝胶分离带Myc-DDK标记的COL6 α2蛋白链,然后用0.15m甘氨酸-盐酸缓冲液(pH 3.0)进行洗脱;
5)透析:利用去离子水对COL6α2洗脱液进行透析;
6)冷冻干燥:对步骤5)进行冷冻干燥,收集COL6α2冻干粉末,即为六型胶原蛋白α2
亚基蛋白。
5.根据权利要求2所述的六型胶原蛋白α2亚基在神经修复产品中的应用,其特征在于,所述的水凝胶的制备方法为:将COL6α2纯化蛋白冻干粉末溶于生理盐水中,配成浓度为1mg/ml的原溶液;将装有COL6α2纯化蛋白的原溶液的容器置于冰盒上,与浓度为10 mg/mL的Matrigel原溶液按1:49的比例混合形成水凝胶;将水凝胶在室温放置5分钟自然凝固。
6.根据权利要求2所述的六型胶原蛋白α2亚基在神经修复产品中的应用,其特征在于,所述的水凝胶的制备方法为:将20μg/mL的COL6α2纯化蛋白溶液与6.9 mg/mL的巯基化透明质酸混合,在混合体系中加入1.8mg/mL的聚乙二醇(二醇)二丙烯酸酯交联反应15分钟凝固成胶。
7.根据权利要求2所述的六型胶原蛋白α2亚基在神经修复产品中的应用,其特征在于,所述的神经移植物的制备方法包括:凝胶灌注、溶液浸泡。
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