CN113956345B - Angpt4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用 - Google Patents
Angpt4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用 Download PDFInfo
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Abstract
本发明涉及生物医药领域,具体涉及ANGPT4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用。本发明发现了ANGPT4蛋白及其编码基因对心脏损伤后的修复与再生能力的关键调控作用,且该作用在哺乳动物中高度保守,有助于推动相关治疗及诊断药物的研发与应用。同时,ANGPT4作为一种分泌蛋白和信号通路配体,为外源递送药物提供了极大便利。而且angpt4突变体不影响发育过程,表明以ANGPT4为靶标调控心脏再生的风险性更小。综上,本发明发现了一种风险性更小、更利于递送、利于时间控制与定量、哺乳动物保守的基因靶标,为治疗人类心血管疾病提供了新的思路。
Description
技术领域
本发明涉及生物医药领域,具体涉及ANGPT4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用。
背景技术
心肌梗塞是当今世界范围内致死率最高的疾病之一(Benjamin et al.,2019;Virani et al.,2020)。心肌梗塞主要由冠状动脉栓塞导致的心肌急性缺血引起,从而造成心肌细胞缺氧坏死或凋亡(Pfeffer and Braunwald,1990;Reeve et al.,2005)。在成年哺乳动物中,受损的心肌不能再生,而是被纤维化的瘢痕组织替代。瘢痕组织能够保持心室壁的完整性,但是大大降低了心脏的收缩能力,最终导致心衰(Frangogiannis,2006;Holmeset al.,2005;Jessup and Brozena,2003;Kehat and Molkentin,2010)。尽管心肌梗塞之后的早期介入治疗可以缓解患者的症状,但是现阶段心肌梗塞的治愈方法只有心脏的移植手术(Augoustides and Riha,2009)。因此,寻找促进心脏再生的方法有助于大大降低心肌梗塞的发病率和死亡率。
目前对促进心脏再生的探索仍然局限在基础研究中。小鼠在出生后一周内很快丧失了其心脏心脏再生的能力。有研究通过单细胞转录组测序探究出生后1天(P1,即具有再生能力)和出生后8天(P8,即不具有再生能力)的小鼠转录组水平的变化,发现与P8小鼠相比,P1小鼠损伤后特异性高表达一系列基因。进一步研究表明,过表达转录因子NFYa和NFE2L1可以促进小鼠心脏损伤后心肌细胞的增殖能力,提高小鼠心脏功能恢复(Cui etal.,2020)。
与哺乳动物不同的是,斑马鱼能够在心脏受损之后快速且有效地再生,而不留下永久的瘢痕组织(Poss et al.,2002)。并且,斑马鱼在心脏发育和功能上与哺乳动物高度相似,是一种很好的研究心脏再生的脊椎动物模型。有研究发现,心脏受损后Nrg1会迅速在心外膜细胞中表达,并且过表达Nrg1会促进斑马鱼心脏损伤后心肌细胞的增殖能力(Gemberling et al.,2015)。然而,在未损伤的斑马鱼中过表达Nrg1会使心肌细胞大量增殖,进而引起心室壁的增厚。同时,在小鼠中过表达NRG1可以促进心肌细胞增殖能力和损伤后的修复(Bersell et al.,2009)。但是,NRG1突变会导致小鼠在胚胎期死亡(Meyer andBirchmeier,1995),表明这一基因在正常发育过程中也有功能。最近在斑马鱼中发现的另一心脏再生调控因子Klf1在心脏受损后特异性上调(Ogawa et al.,2021)。其突变不影响斑马鱼的正常发育,而阻遏斑马鱼的心脏再生。但其过表达会导致斑马鱼心脏在未损伤的情况下出现心衰症状。所以,调控Nrg1和Klf1等基因的表达需要在时间和细胞类型上精确控制,为药物转化增加了难度。
此外,目前以斑马鱼为模式动物发现的基因大多未在哺乳动物中验证,其保守性需要进一步地探究。能够促进哺乳动物心脏损伤后修复能力的基因,基本上都编码胞内蛋白。由于胞内蛋白难以递送至体内,尤其是递送至细胞内,且表达量难以控制,在转化为药物治疗方面存在很大的难度。此外,这些基因中的很大一部分都可能影响本身发育过程,药物转化安全性有待考量。
发明内容
本发明通过对斑马鱼心脏发育和再生过程进行单细胞测序,发现了心脏再生的关键调控因子ANGPT4(Angiopoietin 4,血管生成素4)。ANGPT4在心脏损伤后特异表达,并对心脏再生过程不可或缺。在进一步研究和验证后,本发明提供了ANGPT4蛋白及其编码基因在调控心脏损伤后的修复与再生能力中的应用。
具体而言,本发明首先提供ANGPT4蛋白、或其转录本、或其编码基因、或含有其编码基因的生物材料、或其关键结构域、或其表达促进剂、或其表达抑制剂、或其突变体、或其下游受体促进剂、或其下游受体抑制剂在以下至少一方面的应用:
a)在调控动物或人心脏损伤后的修复与再生能力中的应用;
b)在制备用于调控动物或人心脏损伤后的修复与再生能力的药物中的应用。
当个体表达或过表达ANGPT4蛋白、或促进下游受体时,其在心脏损伤后的修复与再生能力表现为更强;当个体的ANGPT4蛋白的表达受到抑制或抑制其下游受体时,其在心脏损伤后的修复与再生能力表现为更弱。
本发明中所提到的“在调控动物或人心脏损伤后的修复与再生能力中的应用”包括治疗目的的应用、诊断目的的应用以及非诊断治疗目的的应用。其中,治疗目的的应用包括:在预防、减缓、治疗与动物或人心脏损伤相关的疾病或使所述疾病消退中的应用,在减少动物或人心脏损伤后纤维化的瘢痕组织中的应用,等等;诊断目的的应用包括:在预测动物或人心脏损伤后的修复与再生能力中的应用、在检测动物或人心脏损伤情况中的应用,等等;非诊断治疗目的的应用包括:构建心脏再生缺陷动物模型,促进或抑制心肌细胞增殖,等等。
作为促进ANGPT4蛋白表达的一种实施方式,可以在所述心肌细胞中导入过表达ANGPT4基因的腺相关病毒9载体。在具体实施时,也可以在所述心肌细胞中导入表达或过表达ANGPT4基因的其他表达载体或使用表达促进剂的方式来促进ANGPT4蛋白的表达。
作为抑制ANGPT4蛋白表达的一种实施方式,可针对angpt4的第1个外显子设计gRNA,靶点序列为GGGAACGGTCAAGGGAGACGCGG(SEQ ID No.2,序列末尾的“CGG”为PAM区序列),并筛选得到2-bp的缺失突变。突变位点之后的angpt4转录本发生移码突变,并且产生一个提前的终止密码子,进而导致形成一个仅有123个氨基酸残基的无功能的ANGPT4蛋白。在具体实施时,也可以构建大片段缺失突变或通过使用表达抑制剂的方式来抑制ANGPT4蛋白的表达。
另一方面,本发明还提供ANGPT4蛋白、或其转录本、或其编码基因、或含有其编码基因的生物材料、或其关键结构域、或其表达促进剂、或其下游受体促进剂在以下至少一方面的应用:
a)在预防、减缓、治疗与动物或人心脏损伤相关的疾病或使所述疾病消退中的应用;
b)在制备用于预防、减缓、治疗与动物或人心脏损伤相关的疾病或使所述疾病消退的药物中的应用。
优选地,所述疾病为心肌细胞损伤、坏死或凋亡所导致的疾病。
更优选地,所述疾病为缺血性心脏病(包括心肌梗塞)。
另一方面,本发明还提供ANGPT4蛋白、或其转录本、或其编码基因、或含有其编码基因的生物材料、或其关键结构域、或其表达促进剂、或其下游受体促进剂在以下至少一方面的应用:
a)在减少动物或人心脏损伤后纤维化的瘢痕组织中的应用;
b)在制备用于减少动物或人心脏损伤后纤维化的瘢痕组织的药物中的应用。
进一步的,本发明还发现,所述药物通过调控心肌细胞的增殖能力和/或激活内皮细胞中的Tie2-MAPK信号通路来实现对心脏损伤后的修复与再生能力的调控。
作为优选,所述下游受体为Tie2。
另一方面,根据本发明的发现,本领域人员可以将ANGPT4蛋白或其编码基因、或含有其编码基因的生物材料、或其关键结构域应用于预测动物或人心脏损伤后的修复与再生能力的试剂或试剂盒中的应用。
据此,本发明还提供ANGPT4蛋白或其编码基因、或含有其编码基因的生物材料、或其关键结构域在以下至少一方面的应用:
a)在预测动物或人心脏损伤后的修复与再生能力中的应用;
b)在制备用于预测动物或人心脏损伤后的修复与再生能力的试剂或试剂盒中的应用。
若个体可以表达或过表达ANGPT4蛋白时,可推定其在心脏损伤后的修复与再生能力表现为更强;若个体的ANGPT4蛋白的表达受到抑制时,可推定其在心脏损伤后的修复与再生能力表现为更弱。
另一方面,本发明还发现,根据个体体内ANGPT4蛋白的表达可以推测其心脏的受损情况,本领域人员可以在检测动物或人心脏损伤情况对ANGPT4蛋白或其编码基因、或含有其编码基因的生物材料进行应用。
据此,本发明还提供ANGPT4蛋白或其编码基因、或含有其编码基因的生物材料、或其关键结构域在以下至少一方面的应用:
a)在检测动物或人心脏损伤情况中的应用;
b)在制备用于检测动物或人心脏损伤情况的试剂或试剂盒中的应用。
若检测到个体的体内存在ANGPT4蛋白的明显表达(如表达量明显超出常规值),可推定其心脏受到损伤;反之,可推定其心脏未受到损伤。
进一步的,本发明还发现,所述心脏损伤具体为心室损伤。
作为优选,所述动物为哺乳动物,比如可以为小鼠或人。
本发明发现,ANGPT4对心脏再生的调控作用在哺乳动物中高度保守。体外处理ANGPT4重组蛋白可以促进乳大鼠心肌细胞的增殖能力。体内过表达ANGPT4可以促进小鼠心肌梗塞后的心肌细胞增殖能力和功能恢复。
作为优选,所述ANGPT4蛋白或其编码基因源自灵长目、啮齿目、偶蹄目或鲤形目的物种;优选其源自人、猴、小鼠、大鼠、猪或斑马鱼。
进一步优选地,所述ANGPT4蛋白具有以下任意一种氨基酸序列:
1)SEQ ID NO.1或3所示的氨基酸序列;或
2)SEQ ID NO.1或3所示的氨基酸序列经过一个或多个氨基酸残基的替换、缺失或插入获得的具有相同功能蛋白的氨基酸序列。
上述所提到的优选方案也同样能在以下的方法和产品中进行应用。
本发明还提供一种非治疗目的的促进心肌细胞增殖的方法,其包括在心肌细胞内表达或过表达ANGPT4蛋白;
所述表达或过表达ANGPT4蛋白的方式包括:在所述心肌细胞中导入表达或过表达ANGPT4蛋白的载体,和/或,对心肌细胞施用ANGPT4蛋白的表达促进剂;然后对心肌细胞进行体外培养。
本发明还提供一种非治疗目的的抑制心肌细胞增殖的方法,其包括在心肌细胞内抑制或消除ANGPT4蛋白的表达;
所述抑制或消除ANGPT4蛋白的表达的方式包括:在所述心肌细胞中导入抑制或消除ANGPT4蛋白表达的载体,和/或,对心肌细胞施用ANGPT4蛋白的表达抑制剂;然后对心肌细胞进行体外培养。
本发明还提供一种心脏再生缺陷动物模型的构建方法,其包括在对象中抑制ANGPT4蛋白的编码基因的表达,所述抑制可以是心脏特异性的或全局性的。
本发明还提供一种生物材料,其含有ANGPT4蛋白的编码基因;所述生物材料选自表达盒、载体、宿主细胞和重组菌的一种或多种。
本发明还提供一种药物组合物,其含有:
ANGPT4蛋白、或其转录本、或其编码基因、或含有其编码基因的生物材料、或其关键结构域、或其表达促进剂、或其下游受体促进剂中的一种或多种;
以及,药学上可接受、且辅助其用于以下至少一种用途的辅料:1)预防、减缓、治疗与动物或人心脏损伤相关的疾病或使所述疾病消退;2)减少动物或人心脏损伤后纤维化的瘢痕组织。
在一种实施方式中,所述药物组合物含有基因治疗载体以及药学上可接受的辅料;所述基因治疗载体含有能够编码ANGPT4功能蛋白的基因序列和与其可操作性连接的表达调控序列;所述载体可以为质粒载体,病毒载体(如腺病毒载体)或者细菌载体等。
本发明还提供一种试剂盒,其含有用于检测ANGPT4蛋白或其编码基因、或含有其编码基因的生物材料、或其关键结构域中的一种或多种物质的试剂;以用于以下至少一种用途:1)预测动物或人心脏损伤后的修复与再生能力;2)检测动物或人心脏损伤情况。
本发明所提到的生物材料为表达盒、载体、宿主细胞或重组菌。
本领域人员可依照常规方法确定ANGPT4蛋白的关键结构域,如其C端纤维蛋白原结构域。
基于上述方案,本发明的有益效果如下:
本发明发现了ANGPT4蛋白及其编码基因对心脏损伤后的修复与再生能力的关键调控作用,且该作用在哺乳动物中高度保守,有助于推动相关治疗及诊断药物的研发与应用。同时,ANGPT4作为一种分泌蛋白和信号通路配体,为外源递送药物提供了极大便利。而且angpt4突变体不影响发育过程,且在心脏未损伤情况下过表达不会导致心衰症状,表明以ANGPT4为靶标调控心脏再生的风险性更小。综上,本发明发现了一种风险性更小、更利于递送、利于时间控制与定量、哺乳动物保守的基因靶标,为治疗人类心血管疾病提供了新的思路。
附图说明
图1:斑马鱼心脏发育和再生过程中的分子特征。其中,(A)图为所有细胞的t-SNE分群结果,不同形状代表不同细胞亚群。CM-A,心房心肌细胞;CM-V,心室心肌细胞;EC,心内皮细胞;EP,心外膜细胞;EPDC,心外膜衍生细胞。(B)图为经典心脏标记基因的表达量条形图。
图2:斑马鱼发育和再生过程中非心肌细胞的基因表达特征。其中,(A)图为非心肌细胞的t-SNE分群结果,不同形状代表不同的细胞亚群。PC,增殖祖细胞。(B)图为MTZ处理的细胞在各细胞群中的比例。
图3:angpt4突变体斑马鱼具有正常的胚胎发育和心脏形态。其中,(A)图为野生型斑马鱼与angpt4突变体受精后4天(4days post fertilization,dpf)时的胚胎形态。标尺:400μm。(B-C)图为野生型斑马鱼与angpt4突变体胚胎存活率(B)和产卵数(C)的统计分析。ns:p>0.05。(D)图为野生型斑马鱼与angpt4突变体成体心脏形态。标尺:200μm。(E-F)图为野生型斑马鱼与angpt4突变体心室最大截面积(E)和心脏重量与体重比值(F)的统计分析。ns:p>0.05。
图4:angpt4突变体胚胎心脏再生受阻。其中,(A)图具体为MTZ处理后4dpt野生型斑马鱼的心室和心房形态,(B)图具体为angpt4突变体4dpt的心室和心房形态。与野生型相比,angpt4突变体不能再生受损的心室,但心房依然具有正常的形态。
图5:angpt4突变体胚胎心脏损伤后心功能无法恢复。其中,(A-B)图为4dpt野生型和angpt4突变体的心室体积(A)和mCherry荧光强度(B)统计分析。***:p<0.001。(C-D)图为MTZ处理前后(0-4dpt)野生型和angpt4突变体的心室面积改变分数(C)和心房面积改变分数(D)。面积改变分数=(舒张面积-收缩面积)/舒张面积。*:p<0.05。
图6:angpt4突变体成体心脏再生受阻。其中,(A)图为野生型和angpt4突变体成鱼60dpi时的冰冻切片马松三色染色结果。灰色虚线代表伤口区域。(B)图为野生型和angpt4突变体成鱼60dpi时心室纤维化瘢痕区域大小的统计结果。angpt4突变体损伤区域的纤维化瘢痕组织显著大于野生型。(C)图为DMSO处理和Tie2抑制剂处理成鱼30dpi时的冰冻切片马松三色染色结果。灰色虚线代表伤口区域。(D)图为DMSO和Tie2抑制剂处理成鱼30dpi时心室纤维化瘢痕区域大小的统计结果。Tie2抑制剂处理后纤维化瘢痕组织显著增大。标尺:100μm。**:p<0.01。
图7:angpt4在斑马鱼胚胎心脏再生过程中的表达谱。在MTZ处理后1-4dpt和其对应发育时期(4-7dpf)对angpt4进行全胚胎原位杂交染色的结果。箭头指示在1dpt的心脏中能够检测到明显的angpt4的mRNA信号。标尺:100μm。
图8:成体斑马鱼心脏再生过程中angpt4的表达变化。冷冻损伤后1、3、7、14、30dpi及假手术(Sham)的心脏冰冻切片angpt4原位杂交。与Sham相比,angpt4的mRNA信号在1dpi开始上升,3dpi时最高,7dpi之后开始下降至30dpi时达到损伤前水平。灰色虚线代表伤口区域。标尺:100μm。
图9:过表达angpt4促进斑马鱼心脏再生。其中,(A)图为荧光图展示Tg(cmlc2:EGFP-angpt4)转基因鱼系3dpf的EGFP信号。标尺:50μm。(B)图为荧光定量PCR结果显示angpt4在Tg(cmlc2:EGFP-angpt4)中显著上调。**:p<0.01。(C)图为野生型和angpt4突变体成鱼60dpi时的冰冻切片马松三色染色结果。灰色虚线代表伤口区域。标尺:100μm。(D)图为野生型和angpt4突变体成鱼30dpi时心室纤维化瘢痕区域大小的统计结果。过表达angpt4的斑马鱼损伤区域的纤维化瘢痕组织显著小于野生型。**:p<0.01。
图10:重组ANGPT4蛋白促进乳大鼠心肌细胞增殖。其中,(A,B)荧光图展示重组ANGPT4蛋白处理后乳大鼠心肌细胞Ki67或Aurora B染色,α-Actinin染色标记心肌细胞,图中亮色为Ki67或Aurora B信号。标尺:50μm。(C,D)图为不同浓度重组ANGPT4蛋白处理后,乳大鼠心肌细胞Ki67或Aurora B阳性比例统计结果。*:p<0.05;***:p<0.001。
图11:过表达ANGPT4促进小鼠心肌细胞增殖和损伤后功能恢复。图中,(A)图展示Western Blot检测AAV9-ANGPT4或AAV9-GFP注射后三周,小鼠心脏中ANGPT4或GFP的表达。(B)图为过表达GFP或ANGPT4三周后石蜡切片马松三色染色结果,未损伤情况下过表达ANGPT4不影响心脏正常形态。标尺:1000μm。(C)荧光图展示注射AAV9-ANGPT4的小鼠,MI手术2周后Ki67或Aurora B染色结果。cTnT染色标记心肌细胞,图中亮色为Ki67或Aurora B信号。标尺:100μm。(D)图为注射AAV9-ANGPT4或AAV9-GFP的小鼠,MI手术2周后心肌细胞Ki67或Aurora B阳性比例统计结果。*:p<0.05;***:p<0.001。(E)图展示超声结果显示注射AAV9-ANGPT4的小鼠心脏功能恢复较注射AAV9-GFP的小鼠更好。EF:射血分数;FS:缩短分数。Delta%EF表示MI后6周比2周EF的改变数值。Delta%FS表示MI后6周比2周FS的改变数值。*:p<0.05。
具体实施方式
以下实施例用于说明本发明,但不用来限制本发明的范围。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道商购买得到的常规产品。
实施例1 ANGPT4蛋白的功能发现及其在斑马鱼中的功能验证
为了揭示心脏再生过程中的整体分子调控网络,以期寻找能够促进心脏再生的潜在靶点,本发明首先以斑马鱼为模式动物,利用双转基因鱼系Tg(vmhc:mCherry-NTR;amhc:EGFP)诱导心室心肌细胞的特异性损伤,并在损伤后的四个时期和其对应的正常发育时期选取单细胞进行单细胞测序。本发明首先利用所有的心脏细胞进行t分布随机邻接嵌入(t-distributed stochastic neighbor embedding,t-SNE)分析,发现了五种主要的细胞群(图1中A图)。结合已知的心脏经典标记基因,本发明发现这五种细胞类型分别是心房心肌细胞(CM-A)、心室心肌细胞(CM-V)、心内皮细胞(EC)、心外膜细胞(EP)和心外膜衍生细胞(EPDC)(图1中B图)。
已报道的大部分研究主要关注的是调控心肌细胞增殖的基因与信号通路,而心脏中不同类型的细胞是如何共同协作以实现完美再生的尚不明确。非心肌细胞在心脏再生过程中能够提供各种各样的信号,参与形成细胞-细胞之间的调控网络,发挥着十分重要的作用(Gonzalez-Rosa et al.,2011;Kikuchi et al.,2011;Lepilina et al.,2006)。本发明进一步挑选发育和再生过程中的非心肌细胞,进行t-SNE分析。结合已知的经典标记基因,本发明发现非心肌细胞可以分为5个亚群,分别是EC、EP、心外膜衍生细胞群1(EPDC-C1)、心外膜衍生细胞群2(EPDC-C2)和增殖祖细胞群(PC)(图2中A图)。进一步地,本发明发现EPDC-C1同时包括发育和再生状态下的细胞,而EPDC-C2只由MTZ(甲硝唑)处理的细胞构成(图2中B图)。本发明把这群再生特异的EPDC细胞群定义为再生特异细胞群(regeneration-induced cell population,RIC),并利用CRISPR/Cas9系统构建嵌合突变体,进一步筛选在RIC中高表达的基因(Wu et al.,2018)。
在这些基因中,本发明发现angpt4的F0嵌合突变体具有明显的心脏再生缺陷的表型。斑马鱼angpt4基因有两种转录本,编码的ANGPT4蛋白分别包含496或499个氨基酸(其序列如SEQ ID No.1所示),主要功能结构域包括C端纤维蛋白原结构域,参与调控血管新生。为了进一步探究angpt4在斑马鱼心脏再生中的功能,本发明在angpt4的第1个外显子上设计了gRNA,靶点序列为GGGAACGGTCAAGGGAGACGCGG(SEQ ID No.2,序列末尾的“CGG”为PAM区序列),并筛选得到了2-bp的缺失突变。突变位点之后的angpt4转录本发生移码突变,并且产生一个提前的终止密码子,进而导致形成一个仅有123个氨基酸残基的无功能的ANGPT4蛋白。
angpt4的纯合突变体可以存活并且可育。与野生型斑马鱼相比,angpt4突变体的胚胎形态、胚胎存活率和产卵数均没有显著差异(图3中A图-C图)。此外,angpt4突变体具有正常的心脏形态。与野生型斑马鱼相比,angpt4突变体的心室最大截面积和心脏重量也没有显著差异(图3中D图-F图)。该结果表明angpt4突变不影响斑马鱼的心脏发育。
本发明利用MTZ处理Tg(amhc:EGFP;vmhc:mCherry-NTR)的野生型和angpt4突变体胚胎,使心室心肌细胞特异性损伤。在野生型中,处理后一天(1day post treatment,dpt)时心室荧光显著减弱,腔室结构消失,几乎不搏动。之后心室逐渐开始恢复,在3dpt时出现腔室结构并开始搏动,并在4dpt时基本恢复损伤前的水平(图4中A图)。与野生型相比,在MTZ处理前(3dpf),angpt4突变体的心脏没有明显的差异,再次验证了angpt4对心脏的发育没有影响。但是在MTZ处理过后,82枚野生型胚胎中有71枚可以很好地再生损伤的心室,而80枚angpt4突变的胚胎仅有15枚可以再生(图4中B图)。
进一步地,本发明统计了野生型和angpt4突变体胚胎4dpt时的心室体积和mCherry的荧光强度,以及心脏再生过程中(0-4dpt)的心脏功能面积改变(fractionalarea change)。结果显示,与野生型相比,angpt4突变体心室功能在损伤后不能恢复,而心房的功能不受影响(图5)。这些结果表明angpt4对于斑马鱼胚胎心脏的再生具有十分重要的作用。
为了验证angpt4是否对于成体斑马鱼心脏再生是必需的,本发明对野生型和angpt4突变体成鱼进行心室冷冻损伤,并在损伤后60天(60days post injury,dpi)时取出心脏进行冰冻切片。通过对其中最具代表性的切片进行马松三色染色,观察到60dpi时angpt4突变体伤口处纤维化的瘢痕组织显著大于野生型。类似的,抑制ANGPT4下游受体Tie2的活性同样导致瘢痕组织增大(图6)。这表明Tie2在心脏再生过程中十分重要,激活Tie2活性可能可以促进心脏再生能力。
以上结果表明,angpt4突变特异地阻遏了斑马鱼胚胎和成体的心脏再生,而不影响正常的发育过程。为了进一步证明这一结论,本发明首先采用整体胚胎原位杂交技术检测了angpt4在心脏再生前后与再生过程中的表达图谱。结果显示,MTZ处理后1天(1dpt)即可在心脏区域检测到angpt4的明显表达,之后angpt4的mRNA信号逐渐下降,并在损伤后4天完全消失,这与心脏完成再生的时间一致(图7)。相反,在正常发育(未经MTZ处理)的胚胎中则检测不到angpt4的表达。
进一步地,本发明通过冰冻切片原位杂交的方法检测了angpt4在斑马鱼心脏冷冻损伤后不同时期的转录水平。收集斑马鱼心脏冷冻损伤后1、3、7、14、30天(dpi)以及假手术(Sham)的心脏进行冰冻切片,并利用angpt4的探针进行原位杂交。结果显示,在假手术的心脏中基本检测不到angpt4的表达(图8)。冷冻损伤后,angpt4的mRNA最早可以在1dpi时检测到在伤口区域表达,在3dpi时达到最高水平的表达,之后逐渐开始下降,并在30dpi再生基本完成时达到损伤前的水平。这些结果与之前的实验结果相吻合,即angpt4特异在受损的心室中被诱导表达,很可能只在心脏再生中发挥作用。
为了进一步探究angpt4能否促进斑马鱼的心脏再生能力,本发明构建了Tg(cmlc2:EGFP-angpt4)转基因鱼系,在心肌细胞中持续性表达angpt4。在3dpf的转基因胚胎中可以检测到明显的EGFP信号(图9中A图)。荧光定量PCR结果同样显示angpt4在转基因胚胎中显著上调,证明了转基因鱼系过表达angpt4的有效性(图9中B图)。继而在转基因斑马鱼中进行了心室冷冻损伤手术,并在手术后30天统计瘢痕组织大小。结果发现,过表达angpt4的斑马鱼相较于野生型瘢痕组织显著减少(图9中C图,D图)。
实施例2 ANGPT4蛋白在哺乳动物中的功能验证
为了进一步探究ANGPT4促进心脏再生的能力是否在哺乳动物中保守,本发明首先通过体外培养乳大鼠心肌细胞(neonatal rat cardiomyocyte,NRCM)的方式进行检测。在乳大鼠心肌细胞的培养体系中加入不同浓度的重组人源ANGPT4蛋白(氨基酸序列如SEQ IDNo.3所示),并且检测心肌细胞增殖能力。结果发现,ANGPT4蛋白处理可以显著促进乳大鼠心肌细胞Ki67和Aurora B阳性比例,并且ANGPT4浓度越高促进程度越强(图10)。以上结果表明ANGPT4促进心肌细胞增殖的能力在哺乳动物中是高度保守的。
为了进一步探究ANGPT4能否在体内促进哺乳动物心脏功能恢复,本发明构建了过表达人源ANGPT4基因的腺相关病毒9载体(adeno-associated virus 9,AAV9),同时构建了过表达GFP的病毒载体作为对照。通过尾静脉注射的方式将病毒注入成年雄性小鼠(6-8周龄)的循环系统。在尾静脉注射后3周,可以在小鼠的心脏中检测到ANGPT4或EGFP信号,表明腺相关病毒成功感染了小鼠心脏组织(图11中A图)。对过表达三周后小鼠马松三色染色结果显示,未损伤情况下过表达ANGPT4不影响心脏形态(图11中B图)。继而对注射ANGPT4和GFP的小鼠进行了心肌梗塞(myocardial infraction,MI)手术。本发明首先在术后两周通过Ki67和Aurora B染色,来评估小鼠心肌细胞的增殖能力。结果显示,与GFP对照组相比,ANGPT4过表达组的心肌细胞具有明显更高的增殖能力(图11中C图,D图)。更有意思的是,本发明通过超声检测小鼠的射血分数(ejection fraction,EF)和缩短分数(fractionalshortening,FS)发现,与GFP对照组相比,ANGPT4过表达组损伤后的心脏功能恢复到了更高的水平(图11中E图)。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
序列表
<110> 北京大学
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Claims (5)
1.ANGPT4蛋白、或其转录本、或其编码基因、或含有其编码基因的生物材料在制备药物中的应用;所述药物被用于以下至少一方面:
(a)促进小鼠、大鼠、斑马鱼或人心脏损伤后心肌细胞增殖;
(b)减少小鼠、大鼠、斑马鱼或人心脏损伤后的纤维化的瘢痕组织;
所述ANGPT4蛋白的氨基酸序列为SEQ ID NO.1或3所示。
2.根据权利要求1所述的应用,其特征在于,所述心脏损伤为心室损伤。
3.一种非治疗目的的促进心肌细胞增殖的方法,其特征在于,其包括在小鼠、大鼠、斑马鱼或人心肌细胞内过表达ANGPT4蛋白;
所述ANGPT4蛋白的氨基酸序列为SEQ ID NO.1或3所示;
所述过表达ANGPT4蛋白的方式包括:在所述心肌细胞中导入过表达ANGPT4蛋白的载体,然后对所述心肌细胞进行体外培养。
4.一种心脏心室缺陷动物模型的构建方法,其特征在于,其包括在对象中抑制ANGPT4蛋白的编码基因的表达;
所述对象为斑马鱼、小鼠或大鼠;
所述ANGPT4蛋白的氨基酸序列为SEQ ID NO.1或3所示。
5.一种药物组合物,其特征在于,其含有:
ANGPT4蛋白、或其转录本、或其编码基因、或含有其编码基因的生物材料;
以及,药学上可接受、且辅助其用于减少小鼠、大鼠、斑马鱼或人心脏损伤后纤维化的瘢痕组织的辅料;
所述ANGPT4蛋白的氨基酸序列为SEQ ID NO.1或3所示。
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