CN111617254B - 降低mysm1含量或活性的物质在治疗抑郁症中的应用 - Google Patents
降低mysm1含量或活性的物质在治疗抑郁症中的应用 Download PDFInfo
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Abstract
本发明公开了降低MYSM1含量或活性的物质在治疗抑郁症中的应用。本发明的实验证明，MYSM1可以作为抑郁症的治疗靶点：1.抑郁症造模动物内侧缰核MYSM1水平明显升高；2.使用敲除抑郁症造模动物内侧缰核的MYSM1基因后，抑郁样行为得以缓解。MYSM1基因敲除相关试剂可以作为新型抗抑郁药物，内侧缰核区域单次注射可以起到安全持久抗抑郁作用。
Description
技术领域
本发明涉及生物医学领域中，降低MYSM1含量或活性的物质在治疗抑郁症中的应用。
背景技术
抑郁症是神经系统疾病中一类非常常见的疾病。作为影响人类生活最严重的精神疾病之一，抑郁症发病率高。对抑郁症的动物研究、死后大脑分析和影像学研究表明，从病理生理学角度来看抑郁症小鼠的大脑中存在星形胶质细胞功能障碍。抑郁症中，严重抑郁症(Major Depressive Disorder，MDD)，是一个重要的致残原因。MDD的特征是情绪沮丧、无精打采、注意力不集中和自杀倾向的增加。最严重时，抑郁症可引致自杀。虽然对抑郁症已有行之有效的治疗办法，但全球只有不足一半的患者(在一些国家中仅有不到10％的患者)接受有效治疗。目前临床广泛应用的抗抑郁药物，包括单胺氧化酶的抑制剂、三环类药物以及单胺递质重摄取抑制剂等，通过不同的方式延长单胺递质在脑内的作用时效，发挥抗抑郁效果。然而，这类药物产生抗抑郁效果相对缓慢。虽然患者服药后大脑中单胺类神经递质的水平会在几小时内恢复到正常水平，但情绪的改善往往要到几周之后才会发生，无法快速缓解伴有急性自杀风险的抑郁。氯胺酮可以快速抗抑郁，但同时存在较大风险，具有一定的精神依赖性，并且过量可以致死。选择安全有效的抗抑郁药物成为抗抑郁研究重点。
缰核(HB)属于非常保守的脑部结构。在脊椎动物中，从鱼到人大脑中都有，包括内侧缰核(MHB)和外侧缰核(LHB)。缰核对厌恶性和奖赏性刺激有明显反应，被认为介导了人的大部分负面情绪：恐惧、紧张、焦虑。抑郁症小鼠模型中，外侧缰核的簇状放电，产生了抑郁。目前针对内侧缰核特异性抗抑郁药物尚未见报道。
MYSM1，即Myb-Like,SWIRM,and MPN domains 1，是一种组蛋白H2A去泛素化酶，是JAMM/MPN结构域相关的金属蛋白酶家族的一员，能够特异性地使单泛素化组蛋白H2A发生去泛素化，从而起到协同激活作用。目前，关于MYSM1基因的研究较少，主要集中在免疫和造血方向。MYSM1具有非常重要的免疫调控作用，对于T、B细胞、自然杀死细胞、树突状细胞及间充质干细胞等发育、结构和功能发挥重要的调节作用；除此之外，MYSM1缺乏还会导致炎症性肠病的加重、中性粒细胞性脂膜炎等。但MYSM1在神经系统研究鲜有报道，抑郁症中的作用未有相关研究。
发明内容
本发明所要解决的技术问题是如何治疗和/或预防抑郁症。
为解决上述技术问题，本发明首先提供了下述任一应用：
1、降低MYSM1含量或活性的物质在制备治疗抑郁症产品中的应用；
2、抑制MYSM1基因表达或敲除MYSM1基因的物质在制备治疗和/或预防抑郁症产品中的应用。
具体的，所述MYSM1与所述MYSM1基因分别可为小鼠MYSM1蛋白与小鼠MYSM1基因。
上述应用中，所述降低MYSM1含量或活性的物质为能特异识别MYSM1蛋白质的物质。
上述应用中，所述抑制MYSM1基因表达或敲除MYSM1基因的物质为能特异识别MYSM1基因的物质。
上述应用中，所述MYSM1可为缰核MYSM1，所述MYSM1基因可为缰核MYSM1基因。
上述应用中，所述缰核可以以内侧缰核为主。所述缰核可为内侧缰核。
本发明还提供了构建抑郁症动物模型的方法，所述方法包括：提高MYSM1含量或活性，或促进MYSM1基因的表达，得到抑郁症动物模型。
上述方法中，所述方法可通过向动物中导入MYSM1的表达载体或者施加促进MYSM1编码基因表达的物质实现。
上述方法中，所述促进MYSM1编码基因表达的物质可为脂多糖。
所述MYSM1的表达载体可为含有MYSM1基因表达盒的载体，如病毒、质粒、黏粒或噬菌体载体。
所述病毒载体可为腺相关病毒载体。在本发明的一个实施例中，所述腺相关病毒载体为AAV-CMV-Cre。
上述方法中，所述MYSM1可为内侧缰核MYSM1，所述MYSM1基因可为内侧缰核MYSM1基因。
上述方法中，所述缰核可以以内侧缰核为主。
上述方法中，所述动物可为哺乳动物。进一步，所述动物可为小鼠，如C57BL/6小鼠。
在本发明的一个实施例中，所述小鼠为Mysm1tm1c/tm1c鼠。
本发明还提供了治疗抑郁症产品，所述产品含有为A1或A2：
A1、降低MYSM1含量或活性的物质；
A2、抑制MYSM1基因表达或敲除MYSM1基因的物质。
所述产品可以A1或A2为其活性成分，还可将A1或A2与具有相同功能的物质组合在一起作为其活性成分。
上述产品中，所述MYSM1可为内侧缰核MYSM1，所述MYSM1基因可为内侧缰核MYSM1基因。
上述产品中，所述缰核可以以内侧缰核为主。
本文中，所述产品均可为药物。
实验证明，MYSM1可以作为抑郁症的治疗靶点：1.抑郁症造模动物内侧缰核MYSM1水平明显升高；2.使用敲除抑郁症造模动物内侧缰核的MYSM1基因后，抑郁样行为得以缓解。因此，MYSM1基因敲除相关试剂可以作为新型抗抑郁药物，缰核，尤其是内侧缰核区域单次注射可以起到安全持久抗抑郁作用。
附图说明
图1为LPS诱导小鼠FST不动时间显著增加。***表示差异达到显著水平，p＜0.001。
图2为qRT-PCR检测LPS刺激后示脑内各组织炎性因子升高。A、B、C分别为IL1β、TNFα、IL-6的结果。横坐标从左至右依次为MHB、HIP、CPU。LPS-和LPS+分别表示对照组和实验组。*和**表示差异均达到显著水平，分别为p＜0.05和p＜0.01。
图3为冰冻切片免疫荧光检测MYSM1表达情况(免疫荧光标尺75μm)。
图4为抑郁小鼠MHB部位MYSM1敲除后FST/TST不动时间缩短。**表示差异达到显著水平，p＜0.01。
图5为免疫荧光检测MYSM1基因表达量(免疫荧光标尺75μm)。
图6为MHB组织炎性因子基因水平显著下降。图中数字均为两组差异显著性分析p值。
图7为WB检测腺相关病毒感染AST后MYSM1表达情况。
具体实施方式
下面结合具体实施方式对本发明进行进一步的详细描述，给出的实施例仅为了阐明本发明，而不是为了限制本发明的范围。以下提供的实施例可作为本技术领域普通技术人员进行进一步改进的指南，并不以任何方式构成对本发明的限制。
下述实施例中的实验方法，如无特殊说明，均为常规方法，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。下述实施例中所用的材料、试剂、仪器等，如无特殊说明，均可从商业途径得到。以下实施例中的定量试验，均设置三次重复实验，结果取平均值。
下述实施例中的Mysm1tm1c/tm1c小鼠，记载在文献(Forster,M.,Belle,J.I.,et.al.Deubiquitinase MYSM1Is Essential for Normal Fetal Liver Hematopoiesisand for the Maintenance of Hematopoietic Stem Cells in Adult Bone Marrow,STEMCELLS AND DEVELOPMENT,Volume 24,Number 16,2015,1865-77)中，公众可从申请人处获得该生物材料，该生物材料只为重复本发明的相关实验所用，不可作为其它用途使用。Mysm1tm1c/tm1c小鼠背景为C57BL/6小鼠，Mysm1tm1c/tm1c小鼠系衍生自EPD0019_1_A05ES细胞克隆，Mysm1tm1c/tm1c小鼠的MYSM1基因中插入了两个loxp位点，可用于敲除Mysm1基因。
动物饲养和实验符合国家标准和相关要求，小鼠置于在通风的隔离笼中(4-5只/笼)，保证上午7：00-下午7：00的光照，温度保持在21-23℃。动物饲养员每天给动物提供标准食物和水，并密切监测它们的健康和福利。所有动物实验均按照北京军事医学研究院军事认知与脑科学研究所批准的“实验动物的护理和使用指南”进行。
LPS(脂多糖)：Sigma，L-2880。
C57BL/6：北京维通利华实验动物技术有限公司。
实施例1、抑郁模型小鼠的构建
1.抑郁模型小鼠的构建
所用小鼠为基因型鉴定结果显示为纯合子的Mysm1tm1c/tm1c小鼠，将鼠龄为8-12周、体重20-25g的Mysm1tm1c/tm1c小鼠随机分为两组，即实验组和对照组，实验组14只,对照组10只。每天上午9点到10点之间，对实验组的每只小鼠腹腔注射0.5mg/Kg LPS溶液(利用0.9％的生理盐水稀释LPS)各100μl，对对照组的每只小鼠腹腔注射0.9％的生理盐水各100μl，持续10天。至第11天进行评价行为学实验。
2.行为学实验—强迫游泳实验(FST)
完成步骤1后，对照组取10只小鼠，实验组取14只小鼠，将各小鼠分别轻柔地放入盛有水的玻璃烧杯中(直径12cm，高度25cm)，水温为23-25℃，并使其在正常光照下游泳6min。摄像机从烧杯侧面记录动物游泳的具体细节。开始的2min为小鼠的适应期，之后4min进入测试期，记录小鼠的不动时间(Immobility Time)。不动时间被定义为动物保持漂浮或静止不动，仅能保持水中平衡所需的时间。
结果发现连续10d注射LPS后的实验组小鼠不动时间与对照组相比显著增加且具有统计学意义，对照组和实验组的不动时间分别为68.5±9.614sec和134.5±10.12sec。表明LPS可以诱导小鼠抑郁样行为，造模方式可行，后续实验应用连续10d注射LPS后的实验组小鼠作为抑郁模型小鼠。
3.LPS诱导小鼠抑郁导致炎性因子表达升高，MHB中MYSM1表达显著升高
完成步骤1后，每组各取6只小鼠脱颈安乐死后取脑组织(内侧缰核，medialhabenular(MHB)；海马，hippocampus(HIP)；纹状体，caudate putamen(CPU))分别进行qRT-PCR检测炎性因子IL1β、TNFα、IL-6基因的表达情况。
qRT-PCR以β-actin为内参，所用引物序列如下：
qRT-PCR结果显示实验组小鼠脑组织多部位炎性因子IL1β、TNFα、IL-6基因升高(图2)。
完成步骤1后，每组各取4只小鼠取脑组织进行冰冻切片免疫荧光检测MYSM1基因表达情况：
1)取4％PFA心脏灌注所取的脑，固定于15％蔗糖/4％PFA溶液，24小时后置于30％蔗糖PBS溶液中保存。
2)步骤1)完成后，将组织包埋入最佳切割温度(OCT)化合物中，固定于46mm载物台上，冰冻切片机连续切片，40μm厚度，收集在孔板种。
3)步骤2)完成后，进行免疫荧光染色，共聚焦荧光显微镜检测，所用一抗为MYSM1抗体(ab193081，Abcam，1：200稀释)和GFAP抗体(ab10062，Abcam，1：200稀释)(GFAP是胶质纤维酸性蛋白(glial fibrillary acidic protein)的英文简称,是星形胶质细胞活化的标志物)，二抗为羊抗兔CY3单克隆抗体(BA1031，Boster，1:400稀释)和羊抗小鼠FITC单克隆抗体(BA1101，Boster，1:400稀释)。对两组小鼠行取组织行冰冻切片显示，与对照组相比，实验组MYSM1基因在内侧缰核(MHB)中特异性升高(图3)，LPS诱导抑郁模型小鼠内侧缰核区域(MHB)MYSM1基因表达，说明MYSM1基因与MHB区域抑郁相关。
实施例2、抑制MYSM1基因的表达改善了小鼠抑郁，抑制了相关炎性因子基因表达
1.重组病毒的构建
MYSM1基因敲除病毒AAV-CMV-Cre：上海吉凯基因科技有限公司的名称为pAAV-CMVbGlobin-Cre-eGFP的AAV病毒。AAV-CMV-Cre含有eGFP基因与Cre重组酶编码基因，并能表达eGFP蛋白与Cre重组酶。
对照病毒AAV-Con：上海吉凯基因科技有限公司的名称为CON355(9型)的AAV病毒。对照病毒AAV-Con含有eGFP基因，并能表达eGFP蛋白，该病毒与AAV-CMV-Cre的区别在于对照病毒AAV-Con不含有Cre重组酶编码基因。
2.病毒脑内注射
按照实施例1步骤的方法获得抑郁模型小鼠，将所得小鼠随机分为两组，即实验组和对照组，将各小鼠应用阿佛丁avertin(240mg/Kg,Sigma)腹腔内注射麻醉，疼痛刺激小鼠尾部无反应，提示麻醉成功。将小鼠固定于立体定位注射仪(瑞沃德)的门齿固定器上，将AAV-CMV-Cre(滴度1.6×1013/μl)或对照病毒AAV-Con(滴度1.6×1013/μl)注射至小鼠双侧内侧缰核(MHB)(中外侧：±0.25mm，前后：-1.34mm，背腹：-2.75mm)中，每侧注射0.5μl，注射速度为0.4μl/min，实验组小鼠注射AAV-CMV-Cre，对照组小鼠注射对照病毒AAV-Con。每侧注射完成后，留针4min，然后将微量注射器缓慢抽出，缝合皮肤。术后将小鼠放在加热垫上待其从麻醉中恢复。每隔15-20分钟仔细观察动物，以确保所有动物都从麻醉剂中恢复良好。术后14天进行悬尾试验(TST)及强迫游泳实验(FST)。
3.行为学实验
悬尾试验(TST)实验：将小鼠的尾巴在铁架(直径15厘米，高30厘米)上悬吊六分钟，摄像机从侧面记录动物行为的具体细节。开始的1min为小鼠的适应期，之后5min进入测试期，记录小鼠在悬挂期间的不动时间(Immobility Time)。实验组小鼠为7只，对照组小鼠为7只。
FST实验同实施例1步骤2，实验组小鼠为7只，对照组小鼠为7只。
结果发现，与对照组相比，实验组抑郁小鼠不动时间出现了显著下降，表明小鼠抑郁样行为得到显著缓解(图4)。TST实验中对照组和实验组的不同时间分别217.2±13.14sec和154.7±10.1sec；FST实验中对照组和实验组的不同时间分别为153.7±9.596sec和106.9±11.41sec。
4.MYSM1的敲减改善了小鼠抑郁，抑制了相关炎性因子基因表达
病毒脑内注射术后1月，将行为学实验的两组小鼠行脱颈安乐死后取脑组织行qRT-PCR及冰冻切片免疫荧光，qRT-PCR及冰冻切片免疫荧光方法同实施例1。实验组小鼠为7只，对照组小鼠为7只。
冰冻切片免疫荧光结果显示，与对照组相比，实验组小鼠内侧缰核(MHB)中MYSM1表达量均显著下降(图5)。
qRT-PCR检测显示，与对照组相比，实验组MHB组织炎性因子IL1β、TNFα、IL-6基因水平表达显著下降(图6)。
5.星形胶质细胞病毒转染
5.1原代星形胶质细胞培养
星形胶质细胞培养基由向F12-DMEM(Gibco)中添加在培养基中为如下浓度的物质得到：10％(v/v)胎牛血清(FBS)，100U/ml青霉素和100μg/ml链霉素。
(1)取新生24h内的C57BL/6乳鼠，75％的乙醇水溶而言浸泡消毒，无菌条件下取出大脑并置于预冷的PBS液中。解剖显微镜下剥除脑膜及血管，分离出大脑皮层组织。
(2)将大脑皮层组织剪碎后，0.25％胰酶(Gibco)37℃消化5min，然后加入上述星形胶质细胞培养基终止消化，巴氏吸管吹打，100目筛网机械过滤，制备单细胞悬液。
(3)单细胞悬液1000rpm离心5min后，弃上清液，向细胞沉淀中加入上述星形胶质细胞培养基，吹散细胞，转移至被多聚赖氨酸包被的细胞培养皿中，置37℃、5％CO2培养箱中差速贴壁30-60min。
(4)轻轻摇晃细胞培养皿，将细胞悬液吸出至已预先包被多聚赖氨酸的细胞培养皿中。
(5)以后每隔3-4天利用上述星形胶质细胞培养基换液，观察细胞生长状况，培养6-7天，细胞融合成单层。
5.2原代星形胶质细胞的传代培养
(1)弃除培养皿中的旧培养液，用PBS洗涤2次，0.25％的胰酶消化1-2min，并在显微镜下观察细胞情况。
(2)当细胞变圆时，立即用上述星形胶质细胞培养基终止消化，用巴氏吸管吹打，离心后重悬，按1:2接种至新的培养皿中，继续培养。
(3)以后每隔3-4天利用上述星形胶质细胞培养基换液，细胞传至第3代用于实验。
5.3星形胶质细胞转染
选取状态良好的步骤5.2得到的第3代星形胶质细胞(AST)以1.5×105细胞/孔的细胞密度铺板在6孔板上。约70％到80％汇合，所用培养基为上述星形胶质细胞培养基，培养过夜，更换为含有AAV-CMV-Cre或者对照病毒(AAV-Con)的培养基进行病毒的感染，MOI＝106转染。12小时后补液，24小时换液后检测荧光表达,转染效率达60-90％，细胞状态良好，无中毒现象。感染后3天后准备好进行进一步WB实验。
体外分离培养星形胶质细胞(AST)在腺相关病毒转染后WB检测AST(星形胶质细胞)中MYSM1蛋白表达水平，所用一抗为MYSM1抗体(ab193081，Abcam，1：200稀释)，以β-actin为内参，内参抗体为anti-β-actin(sc-47778,Santa Cruz),二抗为山羊抗兔IgG H&L(HRP)(ab97080，Abcam)。与对照组(感染对照病毒)相比，实验组(感染AAV-CMV-Cre)AST中MYSM1表达降低(图7)。
以上对本发明进行了详述。对于本领域技术人员来说，在不脱离本发明的宗旨和范围，以及无需进行不必要的实验情况下，可在等同参数、浓度和条件下，在较宽范围内实施本发明。虽然本发明给出了特殊的实施例，应该理解为，可以对本发明作进一步的改进。总之，按本发明的原理，本申请欲包括任何变更、用途或对本发明的改进，包括脱离了本申请中已公开范围，而用本领域已知的常规技术进行的改变。按以下附带的权利要求的范围，可以进行一些基本特征的应用。
Claims (2)
1.降低MYSM1含量或活性的物质在制备治疗抑郁症产品中的应用；所述降低MYSM1含量或活性的物质为MYSM1基因敲除病毒；所述MYSM1为缰核MYSM1。
2.抑制MYSM1基因表达或敲除MYSM1基因的物质在制备治疗抑郁症产品中的应用；所述抑制MYSM1基因表达或敲除MYSM1基因的物质为MYSM1基因敲除病毒；所述MYSM1基因为缰核MYSM1基因。
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