CN107375910A - PTHrP在制备治疗男性性腺功能低下综合征中的应用 - Google Patents
PTHrP在制备治疗男性性腺功能低下综合征中的应用 Download PDFInfo
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- CN107375910A CN107375910A CN201710567906.5A CN201710567906A CN107375910A CN 107375910 A CN107375910 A CN 107375910A CN 201710567906 A CN201710567906 A CN 201710567906A CN 107375910 A CN107375910 A CN 107375910A
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- related peptide
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Abstract
一种甲状旁腺激素相关肽,具有对生物体血清和睾丸中睾酮偏低的改善或治疗作用,和促进生物体雄性的睾丸间质干细胞的分化的作用。以其作为活性成分在制备治疗男性性腺功能低下综合征药物中的应用。
Description
技术领域
本发明涉及一种多肽在制备治疗疾病药物中的新用途,尤其涉及一种甲状旁腺激素相关肽,在制备治疗男性性腺功能低下综合征中的应用。
背景技术
性腺功能低下综合征(hypogonadism)为男性多发的一种睾丸机能减退,其主要特征包括性欲和勃起质量减退、情绪改变伴有脑力和空间定向能力下降、肌力下降、体毛减少和皮肤改变、骨密度下降以及内脏脂肪增加等(中华男科学杂志[J],2012,18(5),475~477;中华男科学杂志[J],2004,10(8),563~566)。性腺功能低下综合征一般好发于45岁~55岁,也可以早至40岁或延迟到65岁,而发病原因与下丘脑-垂体-睾丸轴系的功能减退和睾丸间质细胞衰退有关(J.Andrology,2009,32(1),1~10;Endocrinology,2002,143(5),1637~1642)。
睾丸间质细胞(Leydig cell)是一种具有合成和分泌睾酮功能的细胞,是雄性体内雄激素的最主要来源。人体血清中的睾酮是间质细胞受脑垂体分泌的促黄体生成激素(Luteinizing hormone,LH)刺激而产生的,并受一系列负反馈机制调节。临床研究表明,男性下丘脑-垂体轴功能随着年龄增长而逐渐下降,从而导致LH脉冲释放的幅度减弱,最终影响睾丸间质细胞合成和分泌雄性激素(内蒙古中医药[J],2012,31(5),117~118)。此外,睾丸间质细胞在分化发育过程中分为四个显著不同的阶段:间质干细胞(Stem Leydigcell)、祖间质细胞(Progenitor Leydig cell)、幼间质细胞(Immature Leydig cell)和成年间质细胞(Adult Leydig cell)。而这些发育过程中由于增殖分化异常、数量减少及激素合成分泌功能减退也会导致体内雄激素缺乏(Proc.Natl.Acad.Sci.USA,2006,103,2719~2724;Mol Cell Endocrinol.2017Apr 15,445,65~73)。
现时,临床上治疗性腺功能低下综合征主要通过睾酮补充疗法,然而,该疗法除了需要定期注射睾酮以外,还存在显著的安全性问题。首先,长期定量补充睾酮会使患者易生痤疮并患红细胞增多症;其次,容易造成血清睾酮浓度的大幅度波动,进而引起患者情绪和迟发性性腺功能低下综合征症状的明显起伏;再次,患者容易出现水、钠潴留及阴茎异常勃起、排尿困难等不良反应,甚至肝肾功能受损及引发前列腺癌等疾病(中国临床保健杂志[J],2009,12(4),386~388;中华男科学杂志[J],2010,16(1),68~71)。
发明内容
本发明的一个目的在于提供一种甲状旁腺激素相关肽,在制备治疗男性性腺功能低下综合征药物中的应用。
本发明的另一个目的在于提供一种甲状旁腺激素相关肽,在制备促进垂体增加LH分泌的药物中的应用。
本发明的再一个目的在于提供一种甲状旁腺激素相关肽,作为诱导试剂,用于诱导睾丸间质干细胞的分化。
本发明的又一个目的在于提供一种组合物,以甲状旁腺激素相关肽为活性成分,制备治疗男性性腺功能低下综合征的药物。
本发明的又一个目的在于提供一种组合物,以甲状旁腺激素相关肽为活性成分,在制备促进垂体增加LH分泌的药物中的应用。
本发明的又一个目的在于提供一种组合物,其中含有甲状旁腺激素相关肽,用于诱导睾丸间质干细胞的分化。
甲状旁腺激素相关肽(PTHrP)是在生命过程中广泛表达的一种分泌性蛋白质。它与甲状旁腺激素(parathyroid hormone,PTH)有一定的同源性(Proc.Natl.Acad.Sci.2006,105,16525~16530)。PTHrP与PTH的氨基端前13位氨基酸中有8个相同,在14~36区域两者的一级结构虽然不同,但空间构象相似,能通过相同的受体PTH1R发挥相似的生物学作用(Mol Endocrinol 2006,20,931~943)。PTH1R与PTH或PTHrP的亲和力几乎相同,属G蛋白偶联受体超家族中B亚族成员,结构较为复杂,有7个跨膜结构、4个胞外区和4个胞内区,胞外区协同穿膜区的螺旋结构,共同参与配体的结合(MolEndocrinol 2006,20,931~943)。PTHrP与受体结合后,通过激活细胞内腺苷酸环化酶-环磷酸腺苷-蛋白激酶A(PKA)途径与磷酯酶C(PLC)-胞浆钙离子-蛋白激酶C(PKC)两条信号转导通路发挥生物学作用(Nat Chem Biol 2009,5,734~742)。PTHrP氨基端1~36区是PKA活化所必需的,它与PTH1R间存在多位点的接触,PTHrP对PKC的激活位点有2个,分别位于28~34区和107~111区。虽然PTH与PTHrP均可结合PTH1R,但前者诱导cAMP持续激活,后者只诱导cAMP短暂激活(Cancer Res 1991,51,6351~6357)
本发明提供的甲状旁腺激素相关肽,用以促进垂体增加LH分泌及诱导睾丸间质干细胞的分化,从而增加睾丸和血清中睾酮含量,最终改善或者治愈男性性功能低下综合征。
本发明的PTHrP来源如:人,小鼠、大鼠,以及重组PTHrP。尤其是如SEQ ID No:1所示的序列。
以本发明提供的PTHrP为主要活性成分制备的治疗男性性腺功能低下综合征组合物的作用包括:
对生物体血清和睾丸中睾酮偏低的改善或治疗作用。即
选取18只雄性Sprague-Dawley大鼠(12~16周龄,250±20克/只,购自温州医科大学实验动物中心)作为研究对象。腹腔注射75mg/kg乙烷二甲烷硫砜(EDS)杀死睾丸间质细胞制造血清无睾酮模型,分3组(每组6只):1)空白(生理盐水);2)PTHrP(10ng/睾丸/天);3)PTHrP(100ng/睾丸/天);将PTHrP用0.9%的生理盐水稀释至0.2微克/毫升(μg/mL)、2微克/毫升(μg/mL),从EDS7天后(此时睾酮为零),每天睾丸内注射(到EDS处理后第28天)。实验结束后,收集血清和睾丸(一半冰冻用于提取RNA进行实时荧光定量多聚核苷酸链式反应(QPCR)和提取蛋白进行蛋白质印迹(WB);另一半Bouin固定液处理用于石蜡切片免疫组织化学),利用化学发光免疫检测血清内睾酮及LH水平。
与对照相比,PTHrP(100ng/睾丸/天)可显著提高血清睾酮水平,而没有影响LH水平。表明,PTHrP作用于睾丸提高睾酮水平。
以本发明提供的PTHrP为主要活性成分制备的治疗男性性腺功能低下综合征组合物的作用还包括:
促进生物体雄性的睾丸间质干细胞的分化。即
将雄性Sprague-Dawley大鼠(12-16周龄,250±20克/只,购自温州医科大学实验动物中心)于实验前7天腹腔注射EDS,二氧化碳窒息处死后,取出睾丸,然后分离曲细精管,把曲细精管分散置于培养板中,50mg(湿重)生精小管/孔(12孔板):一部分对照(组1),一部分加入阳性对照(组2,PDGFAA,10ng/ml),其他加入10、100和1000pg/ml PTHrP(组3-5)进行处理,增加睾丸间质干细胞增殖。3天后,收集曲细精管进行EdU处理;2),用EdU(美国Invitrogen)培养曲细精管16小时,标记增殖细胞,按厂家方案进行荧光显色,用荧光显微镜和数码相机拍照,记录曲细精管外的荧光标记细胞(增殖细胞)。计数增殖的细胞数,以细胞数目/小管面积(cm2)的比值来计算睾丸间质干细胞增殖百分率。
同样分离生精小管,把生精小管分散置于培养板中,50mg(湿重)生精小管/孔(12孔板)。加入0、10、100和1000pg/ml PTHrP合并基础培养基(M199+F12)或睾丸间质细胞分化培养基(LDM)共同培养,共培养2周。每三天换液并收集培养液。第2周末取培养基,测睾酮。一部分曲细精管提取RNA用于QPCR(采用标准曲线法)测量睾丸间质细胞标记物(Lhcgr、Scarb1、Star、Cyp11a1、Hsd3b1、Cyp17a1、Hsd17b3、Cyp2a1和Hsd11b1),一部分提取蛋白用于WB测量睾丸间质细胞标记物(LHCGR、SCARB1、STAR、CYP11A1、HSD11B1、CYP17A1、HSD17B3、CYP2A1和HSD11B1,以及p-CREB和CREB)。在确定一个最佳浓度PTHrP(1000pg/mL)后,一部分曲细精管对照(组1,M199+F12培养基),一部分曲细精管加入PTHrP(1000pg/mL,组2),一部分加H-89(1M,阻断PKA,组3),一部分加U73122(1M,阻断PKC,组4),一部分加1000pg/mlPTHrP+1M H-89(组5)以及1000pg/ml PTHrP+1M U73122(组6),进行同样处理,研究睾丸间质干细胞分化。表明,PTHrP通过PKA-CREB刺激睾丸间质干细胞分化,但对其增殖无影响。此外,睾丸间质干细胞分布在曲细精管表面,且THrP和PTH1R也广泛存在于睾丸组织中,因此,含PTHrP的组合物可通过睾丸静脉注射诱导睾丸间质干细胞进行分化。
本发明的提供的PTHrP多可以通过从自然界生物体中分离、多肽化学合成(Eur.J.Immunol.1994,24,3188-3193;J.Org.Chem.1972,37,3404-3409;多肽合成[P],北京:科学出版社,1985)、原核微生物(如:大肠杆菌)基因工程菌表达后纯化、真核微生物(如:啤酒酵母、毕赤酵母和乳酸克鲁韦酵母等)基因工程菌表达后纯化或由动物细胞(如:中国仓鼠CHO、仓鼠BHK、鼠骨髓瘤细胞小鼠成纤维细胞、猴CV1细胞和人淋巴细胞等)等进行表达并纯化。
本发明提供的PTHrP还包括聚合体,即若干个PTHrP以自动的方式(如:物理吸附)聚集在一起,而形成的集合体。在此情况下,应理解为一种生物自发的自然现象。或者以基因工程方式形成若干个PTHrP相连接的形式。
本发明提供的PTHrP还包括连接体,即采用生物的或化学的连接技术(BioConjugate Chemistry)以人为操作方式实现将PTHrP相互连接在一起。在此情况下,应理解为其有别于生物的自然现象,而是在人为干预的情况下实现。这些技术可以从现有已公开的专利/申请、期刊或论文中了解并实施,如:美国化学协会(ACS)提供的期刊BioConjugate Chemistry。
本发明提供的PTHrP还包括通过化学或生物的手段以共价键或离子键等连接形式进行修饰,如:为了多肽的稳定性、安全性和长效性的目的而进行聚乙二醇化。
本发明所称的组合物,如:药物、食品或保健品等。以其活性成分含有甲状旁腺激素相关肽,以及促黄体生成激素(LH)和神经生长因子(NGF)等。
本发明所称的“食品”是指包括本发明提供的各种化合物、组合物或提取物制成可食用的单一化合物或组合物。该种单一化合物或组合物的生产和制造应当符合相关食品安全标准,但是这些食品安全标准不得限定本发明。
本发明所称的“保健品”是指将包括本发明提供的各种化合物、组合物或提取物制成可食用的单一化合物或组合物以施于患者,起到对疾病进行预防和治疗的目的。其属于本发明所称的食品,但其生产、制造和销售还应当符合各种相关的要求、标准和规范。
本发明所称的“药物”是指可以用于预防或治疗某种疾病的单一化合物、多种化合物形成的组合物、中药材及其提取物,或指以单一化合物为主要活性成分的组合物或制剂(formulation),还指由多种化合物为活性成分的组合物或制剂。“药物”应理解为不仅指根据一国之法律规定,通过其设立的行政机构审批并准予生产的产品,还指在为了获得通过审批和准予生产的过程中,所形成的含单一化合物为活性成分的各类物质形态。“形成”应理解为通过化学合成、生物转化或购买等途径获得。
含有PTHrP的组合物,还包括各种与所含化合物或组合物相适应的药物辅料,以制成有利于给药(drug delivery)的剂型,如:但不仅限于水溶液注射剂、粉针剂、丸剂、散剂、片剂、贴剂、栓剂、乳剂、霜剂、凝胶剂、颗粒剂、胶囊剂、气雾剂、喷雾剂、粉雾剂、缓释剂和控释剂等。这些药用辅料既可以是各种制剂中常规使用的,如:但不仅限于等渗剂、缓冲液、矫味剂、赋形剂、填充剂、粘合剂、崩解剂和润滑剂等;也可以是为了与所述物质相适应而选择使用的,如:乳化剂、增溶剂、抑菌剂、止痛剂和抗氧剂等,这类辅料能有效提高组合物所含化合物的稳定性和溶解性或改变化合物的释放速率和吸收速率等,从而改善各种化合物在生物体内的代谢,进而增强组合物的给药效果。此外,还可以为实现特定的给药目的或方式,如:缓释给药、控释给药和脉冲给药等,而使用的辅料,如:但不仅限于明胶、白蛋白、壳聚糖、聚醚和聚酯类高分子材料,如:但不仅限于,聚乙二醇、聚氨酯、聚碳酸酯及其共聚物等。所称的“有利于给药”的主要表现有:但不仅限于提高治疗效果、提高生物利用度、降低毒副作用和提高患者顺应性等。
在水溶液注射剂中,辅料一般包括等渗剂和缓冲液,以及必要的乳化剂(如:Tweeen-80、Pluronic和Poloxamer等)、增溶剂和抑菌剂等。此外,还包括含有药学上可接受的其它药用辅料,如:抗氧剂、pH调节剂和止痛剂等。
用于制取口服液体制剂的辅料一般包括溶剂,以及必要的矫味剂、抑菌剂、乳化剂和着色剂等。
用于制取片剂的辅料一般包括填充剂(如:淀粉、糖粉、糊精、乳糖、可压性淀粉、微晶纤维素、硫酸钙、磷酸氢钙和甘露醇等)、粘合剂(如:乙醇、淀粉浆、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、明胶溶液、蔗糖溶液和聚乙烯吡咯烷酮的水溶液或醇溶液等)、崩解剂(如:干淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮和交联羧甲基纤维素钠)和润滑剂(如:硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇4,000、聚乙二醇6,000和月桂醇硫酸镁等)等。
用于制取乳剂的辅料一般为水、油(如:脂肪酸)、乳化剂,以及必要的防腐剂和矫味剂等。
用于制取颗粒剂的辅料与片剂类似,但造粒过程不同。根据需要,将制得的颗粒剂与助流剂混合后装入胶囊即得胶囊剂。
本发明所称的“生物体”、“动物”或“患者”是指人、野生动物和家畜(Livestock)。野生动物为自然状态下未经人工驯化的动物。家畜是为了提供食物来源而人工饲养的动物,如:但不仅限于狗、猫、鼠、大鼠、仓鼠、猪、兔、奶牛、水牛、公牛、绵羊、山羊、鹅和鸡等。给予治疗的“患者”或“生物体”优先选择哺乳动物,尤其是人。
附图说明
图1为PTHrP刺激睾丸间质干细胞的分化;其中,图1A是处理曲细精管方案,图1B是免疫荧光标记的曲细精管肌样细胞(SMA)和间质细胞(CYP11A1)和DAPI对染色。曲精小管在LH培养2周,在生精小管周围的染色CYP11A1(箭头),表示睾丸间质细胞,提示有睾丸间质细胞经过培养分化产生;图1C是曲细精管用胰岛素-转铁蛋白-亚硒酸钠培养基添加剂(Insulin-Transferrin-Sodium Selenite,ITS)、LH(5ng/ml),锂(Li,5mM)和ITS+LH+Li处理2周后,收集培养基,采用化学发光免疫检测培养基睾酮水平,试剂盒(货号:L2KTW6,购自浙江国药控股医疗供应链服务有限公司)检测培养基睾酮水平,睾酮水平明显升高提示睾丸间质细胞分化。图1D是曲细精管在含ITS+LH+Li的DMEM/F12培养基(又叫睾丸间质细胞分化培养基,LDM)中培养1周后,加入1000pg/ml PTHrP,继续培养1周,CYP11A1阳性细胞明显增加;图1E是LDM中,加入不同浓度的PTHrP(10pg/ml,100pg/ml,1000pg/ml),在第二周结束时收集培养基测量睾酮水平,100pg/ml和1000pg/ml PTHrP显著增高培养基睾酮水平;图1F是选定一个最佳浓度PTHrP(1000pg/mL)后,曲细精管培养同上,在第二周加入PTHrP(1000pg/mL)和PKA抑制剂H-89(1μM)或PKC抑制剂U73122(1μM)继续培养一周,测量睾酮水平,发现H-89和U73122本身对睾酮不影响,而明显逆转PTHrP(1000pg/mL)诱导的作用,提示PTHrP通过PKA和PKC刺激睾丸间质干细胞分化;图中,Mean±SEM,n=6;“*”表示P<0.05;“**”表示P<0.01;“***”表示P<0.001。
图2为PTHrP上调睾丸间质细胞一些特定基因的表达,其中:LDM中加入PTHrP,其工作浓度分为0pg/ml、10pg/ml、100pg/ml和1000pg/ml。曲细精管在LDM培养至7天,再在培养基中加入不同浓度的0~1000pg/ml PTHrP继续培养至14天,每3~4天更换一次培养基,第14天,收集培养基及曲细精管,曲细精管用于提取RNA,逆转录试剂盒(购自Invitrogen公司)反转录1微克(μg)RNA,采用QPCR检测各个基因的表达情况。0pg/ml组作为对照组,内参为核糖体蛋白S16基因(Rps16,其引物序列由深圳华大基因研究院合成);图中,Mean±SEM,n=6;“*”表示P<0.05;“**”表示,P<0.01Vs对照组;可见PTHrP上调Star、Cyp17a1和Hsd17b3的水平。
图3为PTHrP上调睾丸间质细胞特定蛋白的表达情况,采用Western blot检测相关蛋白(CYP11A1、CYP17A1、17β-HSD3、11β-HSD1)表达情况(左图)。β-ACTIN作为内部参考。图中,Mean±SEM,n=6;“*”表示相对于对照组P<0.05;可见PTHrP上调CYP17A1的水平。
图4为PTHrP刺激间质干细胞的再生时血清睾酮和mRNA变化情况,其中,图4A是从EDS处理7天后,每天睾丸内注射PTHrP到EDS后第28天;图4B是取血、睾丸,一部分睾丸组织用于提取RNA进行QPCR,QPCR测量睾丸间质细胞标记物的表达量。与对照相比,PTHrP(100ng/睾丸/天)可显著提高血清睾酮水平;图4C是对LH水平没有影响;表明PTHrP作用于睾丸,刺激Lhcgr(图4D)和Cyp11a1(图4D)的水平。内参为Rps16。图中,Mean±SEM,n=6;“*”表示相对于对照组P<0.05。
图5为PTHrP刺激睾丸间质细胞的再生的细胞数目情况,大鼠睾丸内注射(到EDS第28天)后,取一只睾丸进行Bouin固定液处理,用于石蜡切片免疫组织化学。睾丸切片染色睾丸间质细胞标记物11β-HSD1和CYP11A1,测量CYP11A1和11-HSD1染色的睾丸间质细胞数目。图5A-C是CYP11A1染色。图5E-G是11-HSD1染色。图5D和H是CYP11A1和11β-HSD1阳性细胞的定量。PTHrP不影响睾丸间质细胞数目。图中,Mean±SEM,n=6。
图6为PTHrP对睾丸间质细胞体积、核体积和质体积的影响,大鼠睾丸内注射PTHrP到EDS第28天后,取一只睾丸进行Bouin固定液处理,用于石蜡切片免疫组织化学。睾丸切片染色睾丸间质细胞标记物CYP11A1,测量CYP11A1阳性睾丸间质细胞体积(图6A)、核体积(图6B)、质体积(图6C);表明PTHrP明显升高睾丸间质细胞细胞体积和质体积(图6A和6C)。
图7 PTHrP对刺激体内间质细胞增生的验证,睾丸切片染色CYP11A1和PCNA(增生标记),在油镜下拍片,测量的CYP11A1与PCNA共同染色的睾丸间质细胞增生。PTHrP不增加PCNA-标记的睾丸间质细胞(图7),提示PTHrP不刺激睾丸间质细胞增生。图7A、图7B和图7C是给予PTHrP的量分别为0ng/睾丸/天、10ng/睾丸/天、100ng/睾丸/天,同时每天睾丸内注射到EDS后至第28天处死采用的组织图CYP11A1与PCNA共同染色的睾丸间质细胞组织图,图7D是PCNA标记的睾丸间质细胞的增殖百分率。。
图8 PTHrP刺激睾丸间质细胞再生的蛋白水平,取一部睾丸组织提取蛋白进行Western blot检测;发现PTHrP刺激LHCGR、SCARB1、CYP11A1、11β-HSD1、CYP17A1等睾丸间质细胞标记物,以及睾丸磷酸化p-CREB和CREB的表达。图中,Mean±SEM,n=6;“*”表示P<0.05;“**”表示P<0.01;“***”表示相对于对照组P<0.001。
具体实施方式
以下结合附图详细描述本发明的技术方案。本发明实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的精神和范围,其均应涵盖在本发明的权利要求范围中。
本发明以下实施例采用的验证方法如下:
实施例1 PTHrP对大鼠睾丸间质细胞的促增殖作用
材料:Corning 12孔板(购自美国康宁公司,货号:3336),睾酮放射性免疫检测试剂盒(购自浙江国药控股医疗供应链服务有限公司,货号:L2KTW6),重组人PTHrP(购自Peprotech公司,货号:96-100-09-100),胰岛素-转铁蛋白-亚硒酸钠培养基添加剂(ITS,购自西格玛奥德里奇上海贸易有限公司,货号:I1884),促黄体生成激素(LH,购自西格玛奥德里奇上海贸易有限公司,货号:L9773),乙烷二甲烷硫砜(EDS,由北京世康合成医药科技有限公司合成), EdU HCS Assays检测试剂盒(购自life technologies公司,货号:C10352),DMEM/F12培养基(购自life technologies公司,货号:0930152DK),Bio-RadcDNA合成试剂盒和Bio-Rad SYBR荧光染料(购自Bio-Rad公司,货号:170-8890、170-8880),总RNA抽提试剂盒(购自QIAGEN公司,货号:74104)。
雄性Sprague-Dawley大鼠(购自温州医科大学动物实验中心,12周龄,250±20克/只)实验前7天腹腔注射EDS(75mg/kg),二氧化碳处死后,将睾丸取出,置于冰冷的磷酸缓冲液中,剪除被膜,将曲细精管分离成单根后,将曲细精管均分至12孔板中,于LDM培养。在37℃,5%二氧化碳的条件下培养2周。在第一周,加入不同浓度的PTHrP处理曲细精管,具体分组为对照组、10、100和1000pg/ml PTHrP。
实施例2 PTHrP对大鼠睾丸间质干细胞的促分化作用
雄性Sprague-Dawley大鼠(12周龄,250±20克/只),实验前7天腹腔注射EDS(75毫克/公斤体重),二氧化碳处死后,将睾丸取出,置于冰冷的磷酸缓冲液中,剪除被膜,血管与曲细精管剥离,将曲细精管分离成单根,将曲细精管均分至12孔板中,于LDM在37℃,5%二氧化碳的条件下培养2周。在第二周,具体分组,加入不同浓度的PTHrP处理曲细精管,具体分组为对照组、10、100和1000pg/ml PTHrP。每3.5天更换一次培养基,收集培养基待测睾酮,收集曲细精管提取RNA,逆转录试剂盒(货号:11753500,购自Invitrogen公司)反转录1微克RNA,42℃逆转录30分钟后,85℃处理5分钟终止反应,40S核糖体蛋白S16基因(40S核糖体蛋白S16基因(RPS16,其引物序列由华大基因合成)作为内参,QPCR和Western blot检测睾酮合成通路上相关基因和酶的表达情况。
实施例3 化学发光免疫法分析培养基中睾酮含量
取雄性Sprague-Dawley大鼠(12周龄,250±20克/只),实验前7天腹腔EDS(75毫克/公斤体重),二氧化碳处死后,将睾丸取出,置于冰冷的磷酸缓冲液中,剪除被膜,血管与曲细精管剥离,将曲细精管分离成单根,将曲细精管均分至12孔板中,在LDM在37℃,5%二氧化碳的条件下培养2周。在第1周,将不同浓度的PTHrP(0~1000pg/ml)加入DMEM/F12培养基中,研究睾丸间质细胞增殖;在第2周,将不同浓度的PTHrP(0~1000pg/ml)加入DMEM/F12培养基中,研究睾丸间质细胞分化。每隔3.5天换一次培养基,第2周末收集培养基,通过化学发光免疫法分析培养基中睾酮含量。
为了进一步分析机制,在确定一个最佳浓度PTHrP(1ng/mL)后,一部分曲细精管对照(组1,M199+F12培养基),一部分曲细精管加入PTHrP(1ng/mL,组2),一部分加H-89(1μM,阻断PKA,组3),一部分加U(1μM,阻断PLC,组4),进行上述同样处理,研究睾丸间质干细胞分化。
实施例4 PTHrP对EDS处理的睾酮低下症的治疗作用
雄性Sprague-Dawley大鼠(12周龄,250±20克/只)18只。腹腔注射75mg/kg EDS,杀死后获得睾丸间质细胞,分3组(每组6只):1)空白(生理盐水);2)PTHrP(10ng/睾丸/天);3)PTHrP(100ng/睾丸/天);从EDS第7天后每天睾丸内注射到EDS第28天。处理动物,取血、睾丸(一半冰冻用于提取RNA进行QPCR和提取蛋白进行WB;另一半Bouin固定液处理用于石蜡切片免疫组织化学)。
序列表
<110> 温州医科大学附属第二医院、温州医科大学附属育英儿童医院
<120> PTHrP在制备治疗男性性腺功能低下综合征中的应用
<141> 2017-07-10
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Claims (10)
1.一种甲状旁腺激素相关肽在制备治疗男性性腺功能低下综合征药物中的应用。
2.根据权利要求1所述的用途,在制备促进垂体增加LH分泌的药物中的应用。
3.根据权利要求1所述的用途,在制备诱导睾丸间质干细胞的分化药物中的应用。
4.根据权利要求1所述的用途,其特征在于所述的甲状旁腺激素相关肽源自人、小鼠、大鼠。
5.根据权利要求1所述的用途,其特征在于所述的甲状旁腺激素相关肽如SEQ ID No 1所示。
6.一种组合物,其特征在于含有甲状旁腺激素相关肽。
7.根据权利要求6所述的组合物,其特征在于所述的甲状旁腺激素相关肽如SEQ ID No1所示。
8.根据权利要求6所述的组合物,作为诱导剂用于诱导睾丸间质干细胞的分化。
9.根据权利要求6所述的组合物,其特征在于所述的组合物为药物、食品和保健品。
10.根据权利要求6所述的组合物,其特征在于还包括促黄体生成激素和神经生长因子之一种或几种。
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