CN101873866B - 代谢综合症的治疗或预防剂、检查方法、检查药、以及代谢综合症的治疗药的候选化合物的筛选方法 - Google Patents
代谢综合症的治疗或预防剂、检查方法、检查药、以及代谢综合症的治疗药的候选化合物的筛选方法 Download PDFInfo
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Abstract
本发明提供一种可提高在生物体内的稳定性的代谢综合症的治疗或预防剂、检查方法、检查药、以及代谢综合症的治疗药的候选化合物的筛选方法。该代谢综合症的治疗或预防剂含有作为有效成分的编码受体活性修饰蛋白(RAMP)2的以下(a)到(d)中任意一个所述的DNA、或者该DNA编码的多肽:(a)具有序列号1所述的碱基序列的DNA;(b)具有能够在严紧条件下与序列号1所述的碱基序列杂交的碱基序列的DNA;(c)具有编码在序列号2所述的氨基酸序列中将一个或多个氨基酸取代、缺失和/或插入后的氨基酸序列的碱基序列的DNA;(d)由与序列号1所述的碱基序列具有90%以上的相同性的碱基序列构成的DNA。
Description
技术领域
本发明涉及一种代谢综合症的治疗或预防剂、检查方法、检查药、以及代谢综合症的治疗药的候选化合物的筛选方法。
背景技术
近年来,代谢综合症的患者以发达国家为中心急速增加。所谓的代谢综合症,是指内脏脂肪型肥胖(内脏肥胖、腹部肥胖)与高血糖、高血压以及高血脂中的两种以上并发的复合生活习惯病。由于相关的复合症状,代谢综合症是促进心脏病、脑卒中等的进程以及老年人的健康寿命和QOL显著恶化的最大原因。在这样的背景下,为了维持全社会的活力以及减少医疗成本,代谢综合症的征服和抑制成为大的社会需求。
作为联系代谢综合症与动脉硬化、血管并发病、器官功能障碍发病之间的重要的分子基础,脂肪因子(adipokine)等具有多样的生理活性的体液因子引起了人们的关注。体液因子也在脂肪组织以外的各种外周器官中产生,一方面,这些外周器官通过体液因子密切配合以维持生物体内的动态平衡,另一方面,体液因子的平衡的破坏也是动脉硬化和器官功能障碍发病的原因之一。作为体液因子家族之一,本发明人关注了肾上腺髓质素(AM)及其受体活性调节蛋白(RAMP)系统。
肾上腺髓质素(AM)是在以血管为代表的全身组织产生的肽。已经明确了除了血管扩张作用以外,AM还具有体液量调节作用、激素分泌调节作用、抗氧化作用、抗炎作用等多样的生理活性。至此,本发明人报道确认了AM敲除小鼠的杂合子血压上升,对心血管系统施加损伤时的心肥大、纤维化、肾功能低下、动脉硬化恶化,与此相对,确认了AM过量表达的小鼠血压反而降低,显示出了对器官损伤和动脉硬化的抵抗力,因此,AM具有器官保护作用、抗动脉硬化作用。(参照非专利文献1-3)。
另外,AM敲除小鼠的纯合子由于血管发育不充分,在胎生中期因为弥漫性出血和浮肿而死亡,据此,本发明人首次明确了AM是血管成熟、血管结构的稳定化所必需的物质(参照非专利文献4)。而且,最近报道了血中AM浓度伴随着肥胖而上升,与身体质量指数相关,以及AM也在脂肪组织中表达,该表达在肥胖状态下亢进(参照非专利文献5、6)。另一方面,观察到AM敲除小鼠随着年龄的增长,伴随着肥胖、耐糖量异常、以及生物体内氧化应激亢进,器官损害也进展,暗示了AM与代谢综合症之间的关联性。
非专利文献1:Shindo T et al.Circulation.2000
非专利文献2:Imai Y.Shindo T et al.ATVB.2002
非专利文献3:Niu P,Shindo T et al.Circulation.2004
非专利文献4:Shindo T et al.Circulation.2001
非专利文献5:Kato J et al.Hypertens Res.2002
非专利文献6:Numbu T et al.Regul Pept.2005。
发明内容
但是,AM由于血中半衰期短,因此用作慢性疾病代谢综合症的治疗药存在很多制约。
鉴于以上事实,本发明的目的是提供一种能够提高在物体内的稳定性的代谢综合症的治疗或预防剂。另外,本发明的目的还在于提供一种代谢综合症的检查方法和检查药、以及代谢综合症的治疗药的候选化合物的筛选方法。
本发明人在深入研究的过程中,关注了AM的受体系统。AM受体本体是属于G蛋白偶联型受体B族的称作CRLR(降钙素受体样受体)的七次跨膜型受体。CRLR与一次跨膜型蛋白RAMP(受体活性修饰蛋白)1、2、3亚型异构体(サブァィソフォ一ム)中的任意一者结合,形成异二聚体。
本发明人通过适当改变结合在CRLR上的RAMP的亚型异构体,发现可以控制AM受体和配体的亲和性,从而完成本发明。具体地本发明提供了以下内容。
(1)、一种代谢综合症的治疗或预防剂,其中,该代谢综合症的治疗或预防剂含有作为有效成分的编码受体活性修饰蛋白(RAMP)2的以下(a)到(d)中任意一个所述的DNA、或者该DNA编码的多肽,
(a)具有序列号1所述的碱基序列的DNA;
(b)具有能够在严紧条件下与序列号1所述的碱基序列杂交的碱基序列的DNA;
(c)具有编码在序列号2所述的氨基酸序列中将一个或多个氨基酸取代、缺失和/或插入后的氨基酸序列的碱基序列的DNA;
(d)由与序列号1所述的碱基序列具有90%以上的相同性的碱基序列构成的DNA。
(2)、一种代谢综合症的检查方法,其中,该方法包括:
从受试者的细胞中提取DNA的提取步骤;
扩增步骤,以提取的所述DNA为模板,使用能够特异性扩增由序列号3所述的碱基序列构成的DNA或其表达控制区域的DNA的一部分或全部的引物进行聚合酶链反应;
对扩增的DNA的碱基序列进行测序的测序步骤;
比较测序后的碱基序列和序列号3所述的碱基序列的比较步骤。
(3)、一种代谢综合症的检查药,其中,所述检查药的有效成分是能够特异性扩增由序列号3所述的碱基序列构成的DNA或其表达控制区域的一部分或全部的引物、或者与由序列号2所述的氨基酸序列构成的多肽特异性结合的抗体或抗体片段。
(4)、一种代谢综合症的治疗药的候选化合物的筛选方法,其中,该方法包括:
使序列号2所述的氨基酸序列、或者具有在序列号2所述的氨基酸序列中将一个或多个氨基酸取代、缺失和/或插入后的氨基酸序列的多肽与被检测物接触的步骤;
检测所述多肽和所述被检测物的结合的步骤。
(5)、一种代谢综合症的治疗药的候选化合物的筛选方法,其中,该方法包括:
对内源性RAMP2基因变异或敲除的动物给与被检测物的步骤;
检测代谢综合症的症状改善的步骤。
(6)、一种代谢综合症的治疗药的候选化合物的筛选方法,其中,该方法包括:
使表达具有序列号1所述的碱基序列的DNA、具有能够在严紧条件下与序列号1所述的碱基序列杂交的碱基序列的DNA、或者由与序列号1所述的碱基序列具有90%以上的相同性的碱基序列构成的DNA的细胞与被检测物接触的步骤;
检测所述DNA的表达量的变化的步骤。
(7)、一种代谢综合症的治疗药的候选化合物的筛选方法,其中,该方法包括:
使表达具有序列号1所述的碱基序列的DNA、具有能够在严紧条件下与序列号1所述的碱基序列杂交的碱基序列的DNA、或者由与序列号1所述的碱基序列具有90%以上的相同性的碱基序列构成的DNA的细胞与被检测物接触的步骤;
检测从所述DNA合成的蛋白质的细胞内局部存在的变化的步骤。
(8)、一种代谢综合症的治疗药的候选化合物的筛选方法,其中,该方法包括:
使序列号6所述的氨基酸序列、或者具有在序列号6所述的氨基酸序列中将一个或多个氨基酸取代、缺失和/或插入后的氨基酸序列的多肽、可分解该多肽的酶、以及被检测物共存的步骤;
测量在规定时间后的所述多肽的残留量的步骤;
比较残留量的测量值与在不存在所述被检测物下测量的残留量的步骤。
(9)、一种代谢综合症的治疗药的候选化合物的筛选方法,其中,该方法包括:
使表达具有序列号1所述的碱基序列的DNA、具有能够在严紧条件下与序列号1所述的碱基序列杂交的碱基序列的DNA、或者由与序列号1所述的碱基序列具有90%以上的相同性的碱基序列构成的DNA、并且表达具有序列号4所述的碱基序列的DNA、具有能够在严紧条件下与序列号4所述的碱基序列杂交的碱基序列的DNA、或者由与序列号4所述的碱基序列具有90%以上的相同性的碱基序列构成的DNA的细胞与被检测物接触的步骤;
检测由具有序列号5所述的碱基序列的DNA编码的配体的刺激引起的细胞内信号传导的诱导、或者由所述配体的刺激引起的G蛋白的活化的步骤。
根据本发明,由于在体内给与RAMP2或其功能等同物,因此可以有效地治疗或预防代谢综合症。而且,RAMP2或其功能等同 物为膜蛋白,因此具有较长的血中半衰期,可以提高在生物体内的稳定性。
附图说明
图1是从RAMP2+/-、由ob/ob小鼠提取的肝脏的HE染色照片(a)、以及油红O染色照片(b);
图2是RAMP2+/-小鼠的大腿动脉及其周围的切片照片(a)、以及大动脉局部放大图(b);
图3是RAMP2+/-小鼠的大腿动脉切片照片;
图4是示出RAMP2+/-小鼠的大腿动脉中的各基因的表达量的图表;
图5是RAMP2+/-小鼠的其它大腿部切片照片;
图6是示出RAMP2+/-小鼠的大腿动脉的血栓量的图表;
图7是示出RAMP2+/-小鼠的大腿动脉的血管狭窄量的图表;
图8是RAMP2+/-小鼠的其它大腿部切片照片;
图9是用于特异性敲除内皮细胞的RAMP2基因的载体的简图;
图10是示出来自血管内皮细胞特异性RAMP2敲除小鼠的细胞中的RAMP2基因的表达量的图表;
图11是从血管内皮细胞特异性RAMP2敲除小鼠提取的肺的染色照片(a)、以及其局部放大图(b);
图12是从血管内皮细胞特异性RAMP2敲除小鼠提取的肾脏的外观照片(a)、截面照片(b)、以及切片的染色照片(c);
图13是图12(c)的局部放大图;
图14是用于特异性敲除心肌细胞的RAMP2的其它载体的简图;
图15是从心肌细胞特异性RAMP2敲除小鼠提取的心脏的外观照片(a)、以及切片的染色照片(b);
图16是图15(b)的局部放大图;
图17是示出图15的心脏的心肌细胞的横径的图表。
具体实施方式
以下对本发明的一个实施方式进行说明。
<治疗药、预防药>
本发明的代谢综合症的治疗或预防药含有作为有效成分的编码受体活性修饰蛋白(RAMP)2的以下(a)到(d)中任意一个所述的DNA、或者该DNA编码的多肽,
(a)具有序列号1所述的碱基序列的DNA;
(b)具有能够在严紧条件下与序列号1所述的碱基序列杂交的碱基序列的DNA;
(c)具有编码在序列号2所述的氨基酸序列中将一个或多个氨基酸取代、缺失和/或插入后的氨基酸序列的碱基序列的DNA;
(d)由与序列号1所述的碱基序列具有90%以上的相同性的碱基序列构成的DNA。
另外,本说明书中的“代谢综合症”是指内脏脂肪型肥胖(内脏肥胖、腹部肥胖)与高血糖、高血压以及高血脂中的两种以上并发的状态,包括动脉硬化、缺血性疾病(心肌梗塞、心绞痛、脑梗塞、动脉硬化闭塞症)、血管功能不全、器官功能不全等的并发症,或者设想为这些并发症的原因之一。
本发明中的“DNA”可以为正义链或反义链(例如,可以作为探针使用),其形状可以是单链或双链。另外,可以是基因组DNA,也可以是cDNA或合成DNA。
本发明的DNA的最优选的形式是具有序列号1所述的碱基序列的DNA,但是本发明的DNA还括具有代谢综合症的治疗或预防效果的各种变异体或同源体。在此,“代谢综合症的治疗或预防效果”是指改善内脏脂肪型肥胖(内脏肥胖、腹部肥胖)、高血糖、高血压、高血脂中的至少一种症状或者抑制症状恶化的效果,是指统计学上有意义的改善或抑制的效果。
序列号1为编码人RAMP2的细胞外区域的碱基序列。具有该序列号1所述的碱基序列的DNA的变异体或同源体包括例如具有能够在严紧条件下与序列号1所述的碱基序列杂交的碱基序列的DNA。在此,作为“严紧条件”,例如可列举出这样的条件,即,在通常的杂交缓冲液中在40~70℃(优选为60~65℃)下进行反应,在盐浓度为15~300mM(优选为15~60mM)的洗涤液中进行洗涤。
另外,已知序列号2构成了人RAMP2蛋白的细胞外区域(Trends in Biochemical Science,Vol.31,No.11,pp.631-638)。还包 括具有编码在该序列号2所述的氨基酸序列中将一个或多个氨基酸取代、缺失和/或插入后的氨基酸序列的碱基序列的DNA。在此,“一个或多个”通常为50个氨基酸以内,优选为30个氨基酸以内,更优选为10个氨基酸以内(例如,5个氨基酸以内、3个氨基酸以内、1个氨基酸)。在维持活化肌特异性酪氨酸激酶的能力的情况下,变异的氨基酸残基优选变异为保留氨基酸侧链的性质的其它的氨基酸。例如,按照氨基酸侧链的性质,可以列举出疏水性氨基酸(A、I、L、M、F、P、W、Y、V)、亲水性氨基酸(R、D、N、C、E、Q、G、H、K、S、T)、具有脂肪族侧链的氨基酸(G、A、V、L、I、P)、具有含羟基的侧链的氨基酸(S、T、Y)、具有含硫原子的侧链的氨基酸(C、M)、具有含羧酸和氨基的侧链的氨基酸(D、N、E、Q)、具有含碱性基团的侧链的氨基酸(R、K、H)、具有含芳香族基团的侧链的氨基酸(H、F、Y、W)(括号内均表示氨基酸的一字母标记)。
对于具有通过相对于某氨基酸序列将一个或多个氨基酸残基缺失、插入和/或被其它氨基酸取代而修饰的氨基酸序列的蛋白质,已知其生物学活性被保持(Mark,D.F.et al.,Proc.Natl.Acad.Sci.USA(1984)81,5662-5666、Zoller,M.J.& Smith,M.Nucleic AcidsResearch(1982)10,6487-6500、Wang,A.et al.,Science 224,1431-1433、Dalbadie-McFarland,G.et al.,Proc.Natl.Acad.Sci.USA(1982)79,6409-6413)。
而且,具有序列号1的碱基序列的DNA的变异体或同源体中还包括由与序列号1所述的碱基序列具有较高相同性的碱基序列构成的DNA。这样的DNA优选与序列号1所述的碱基序列具有90%以上、更优选具有95%以上(96%以上、97%以上、98%以上、99%以上)的相同性。氨基酸序列或碱基序列的相同性可以由Karlin-Altschul算法BLAST(Proc.Natl.Acad.Sci.USA 90: 5873-5877,1993)确定。基于该算法,开发了称作BLASTN或BLASTX的程序(Altschul et al.J.Mol.Biol.215:403-410,1990)。在基于BLAST根据BLASTN来解析碱基序列时,参数例如为score=100、wordlength=12。另外,在基于BLAST根据BLASTX来解析氨基酸序列时,参数例如为score=50、wordlength=3。在使用BLAST和Gapped BLAST程序时,使用各程序的默认参数。这些解析方法的具体方法是公知的(http://www.ncbi.nlm.nih.gov.)。
本发明获取DNA的方法没有特别的限定,可以列举出通过从mRNA逆转录来得到cDNA的方法(例如RT-PCR法)、从基因组DNA调整的方法、通过化学合成进行合成的方法、从基因组DNA文库或cDNA文库分离的方法等公知的方法(例如参照日本特开平11-29599号公报)。
<多肽>
本发明的治疗或预防剂中使用的多肽由所述DNA编码,例如具有序列号2所述的氨基酸序列、或者具有在序列号2所述的氨基酸序列中将一个或多个氨基酸取代、缺失和/或插入后的氨基酸序列。
上述多肽由于不具有人RAMP2蛋白质的跨膜区域和细胞内区域的全部,因此期待具有高的可溶性,能够用以下方法等容易地精制。另外,RAMP2的细胞外区域是用于与CRLR结合形成复合体所必需的(数据未显示)。因此,上述多肽与给与了该多肽的细胞膜上的CRLR形成复合体,发挥代谢综合症的治疗或预防效果。
本发明的DNA所编码的多肽例如可以通过使用导入有含有所述DNA的表达载体的转化子来制备。即,首先在适当的条件下培养该转化子,以合成该DNA编码的蛋白质(多肽)。然后,通过从转化子或培养液回收合成的蛋白质,可以得到本发明的多肽。
对于转化子的培养,为了大量且容易地获得多肽,可以根据转化子的种类等从公知的培养基适当选择,并适当调整培养基的pH、培养时间等(例如参照日本特开平11-29599号公报)。
作为多肽的分离方法和精制方法,没有特别的限定,可以列举出利用溶解度的方法、利用分子量的差的方法、利用电荷的方法等公知的方法(例如参照日本特开平11-29599号公报)。以下说明能在本发明中使用的载体和转化子。
(载体)
可以通过在适当的载体中插入上述DNA来制备表达载体。所谓的“适当的载体”,只要是在原核生物和/或真核生物的各种宿主中能够保持复制或能够自我增殖的载体即可,可以根据使用的目的进行适当选择。例如,想要大量获得DNA时,可以选择高复制载体,想要获得多肽时,可以选择表达载体。作为具体例,没有特别的限定,例如可以列举出日本特开平11-29599号公报中所述的公知的载体。
(转化子)
可以通过在宿主中导入含有所述DNA的载体来制作转化子。这样的宿主只要是适于被本发明的载体转化的宿主即可,作为其具体例子没有特别的限制,可以列举出细菌、酵母、动物细胞、昆虫细胞等的公知的天然细胞或人工建立的细胞(参照日本特开平11-29599号公报)。
载体的导入方法可以根据载体或宿主的种类等适当选择。作为其具体例子没有特别的限制,可以列举出原生质法、感受态(competent)法等公知的方法(例如参照日本特开平11-29599号公报)。
本说明书中的“有效成分”是指用于得到代谢综合症所希望的治疗或预防效果而以必要的量所含有的成分,在不满足所希望的水平之前只要不损害效果还可以含有其它成分。另外,药物组合物的给药途径可以是口服或非口服,可以适当设定。
口服给药时,药物组合物可以含有一般使用的添加剂,如粘合剂、包含剂、赋形剂、润滑剂、崩解剂、润湿剂,并制剂化为片剂、颗粒剂、细粒剂、散剂、胶囊剂等各种形状。另外,药物组合物可以是内服水剂、悬浊剂、乳剂、糖浆剂等液体状态,也可以是使用时再溶解的干燥状态。
非口服给药时,药物组合物可以含有稳定剂、缓冲剂、保存剂、等渗剂等的添加剂,通常以被收容于在单位给药量安瓿或多给药量容器或软管内的状态流通。另外,药物组合物还可以制剂成可在使用时用适当的介质(无菌水等)再溶解的粉体。
<检查方法、检查药>
所述DNA可以在针对代谢综合症的罹患的有无的检查中利用。本发明所涉及的代谢综合症的检查方法包括提取步骤、扩增步骤、测序步骤、以及比较步骤。
在提取步骤中,从受试者的细胞提取DNA。提取的方法使用常规的方法即可。
在扩增步骤中,以提取的DNA为模板,使用能够特异性扩增由序列号3所述的碱基序列构成的DNA或其表达控制区域的DNA的一部分或全部的引物进行聚合酶链反应。由此,特异性扩增具有序列号3的一部分或全部的DNA。另外,序列号3为人RAMP2基因的全碱基序列。
在测序步骤中,测序被扩增的DNA的碱基序列,在比较步骤中,比较被测序的碱基序列和序列号3所述的碱基序列。碱基序列的测序和比较可根据常规方法进行。当比较的结果显示取得的DNA的碱基序列与序列号3不同时,可以判断疑似者已经或者容易罹患代谢综合症。
并且,本发明的检查方法还可以包括判断步骤,用于例如将在扩增步骤中被扩增的DNA导入RAMP2变异或敲除的细胞、组织、器官或者个体中,并进一步判断属于代谢综合症的症状是否被改善,或者恶化是否被抑制。由此,由于可以排除被扩增的DNA的碱基序列和序列号1所述的碱基序列的差异为单一的多态性的情况等,因此可以提高检查精度。
(敲除体)
通过变异或敲除所述DNA,可以制作非人转化细胞、组织、器官以及个体。作为非人动物没有特别的限制,可以列举出小鼠、大鼠、豚鼠、仓鼠、兔子、山羊、猪、狗、猫等。
非人转化动物的制作方法例如如下所述。首先,将本发明的DNA、DNA的变异、或者与DNA相同重组的DNA导入非人哺乳动物的受精卵中。然后,将该受精卵移植到雌性个体子宫中发育,从而制作转化了本发明的DNA的非人转化动物。
更具体地,例如可以如下地制作非人转化动物。首先,使通过给与激素而过量排卵后的雌性个体与雄性个体交配。然后,由交配后第一天的雌性个体的输卵管取出受精卵,用显微注射等方法将含有变异的DNA、或者可与DNA相同重组的DNA的载体导入受精卵中。然后,用适当的方法培养导入后的受精卵后,将生存的受精卵移植到假妊娠的雌性个体(假亲)的子宫中,生出新生仔。可以 通过对由该新生仔的细胞提取的DNA进行DNA印迹解析来确认该新生仔中DNA是否被转化。
除此之外,还可以在胚胎干细胞(ES细胞)株中进行基因导入和选择后,制作对在生殖系统有用的嵌合体动物,通过交配,制作非人转化动物。
其它检查方法包括:检测具有来自于受试者的细胞中的序列号1所述的碱基序列的DNA的表达量的检测步骤、以及比较检测的DNA的表达量与健康者的序列号1所述的DNA的表达量的比较步骤。
在此,“DNA的表达”包括转录水平(mRNA的表达)和翻译水平(蛋白质的表达)。因此,表达量可以通过使用能够特异性扩增具有序列号1所述的碱基序列的一部分或全部的DNA的引物,通过进行定量RT-PCR而进行检查,也可以通过使用特异性地结合由序列号2所述的氨基酸序列构成的多肽的抗体或抗体片段,通过蛋白印迹解析等而进行检测。
根据该检查方法,当比较的结果显示受试者的DNA的表达量与健康者的DNA的表达量有意义地不同时,可以判断疑似者已经或者容易罹患代谢综合症。
本发明中的代谢综合症检查药含有作为有效成分的能够特异性地扩增具有编号1所述的碱基序列的一部分或全部序列的DNA的引物、或者上述抗体或抗体片段。
<筛选方法>
本发明涉及的代谢综合症的治疗药的候选化合物的筛选方法包括对内源性RAMP2基因敲除的动物给与被检测物的步骤、以及检测代谢综合症的症状改善的步骤。
根据该筛选方法,由于被检测出症状改善的被检测物可以补充或代替RAMP2的功能,因此可以指定为代谢综合症的治疗药的候选化合物。
其它的筛选方法包括:使表达具有序列号1所述的碱基序列的DNA、具有能够在严紧条件下与序列号1所述的碱基序列杂交的碱基序列的DNA、或者由与序列号1所述的碱基序列具有90%以上的相同性的碱基序列构成的DNA的细胞与被检测物接触的步骤;以及检测所述DNA的表达量的变化的步骤。
可以推测检测出序列号1等的DNA的表达量的变化的被检测物能够强化或减弱RAMP2的功能。具体地,由于DNA表达量增加的物质能够强化RAMP2的功能,因此推测被给药时能够治疗代谢综合症。另一方面,降低DNA表达量的物质由于能够减弱RAMP2的功能,因此推测可以通过给与拮抗该物质的物质来治疗代谢综合症。
另外,在该方法和以下的方法中使用的细胞可以表达也可以不表达内源性RAMP2。但是,在可以将内源性RAMP2造成的不明确的影响排除在外这一点上,优选不表达内源性RAMP2的细胞(例如COS7)。
其它的筛选方法包括:使具有序列号2所述的氨基酸序列、或者在序列号2所述的氨基酸序列中将一个或多个氨基酸取代、缺失和/或插入后的氨基酸序列的多肽与被检测物接触的步骤;以及检测所述多肽和所述被检测物的结合的步骤。
根据该筛选方法,可以得到结合在序列号2等的多肽上的被检测物。推测该被检测物可能与序列号2等的多肽参与的代谢综合症的治疗路径相关,可以治疗代谢综合症。
其它的筛选方法包括:使表达具有序列号1所述的碱基序列的DNA、具有能够在严紧条件下与序列号1所述的碱基序列杂交的碱基序列的DNA、或者由与碱序列号1所述的碱基序列具有90%以上的相同性的碱基序列构成的DNA的细胞与被检测物接触的步骤;以及检测由所述DNA合成的蛋白质的细胞内局部存在的变化的步骤。
根据该筛选方法,可以得到使由序列号1等合成的蛋白质的细胞内局部存在变化的被检测物。在此,在AM和受体结合后,RAMP2才与受体一起通过内吞作用而摄入细胞内,如果没有由外部向AM的刺激,只要产生存活,就可以持续在细胞膜上稳定存在。另外,可以推测即使通过内吞作用被暂时摄入细胞内,但其一部分再次返回到细胞膜再利用。因此得到的被检测物具有能够提高RAMP2参与的代谢综合症的治疗效果的可能性,可以期待作为代谢综合症的治疗药。
其它的筛选方法包括:使序列号6所述的氨基酸序列、或者具有在序列号6所述的氨基酸序列中将一个或多个氨基酸取代、缺失和/或插入后的氨基酸序列的多肽、可分解该多肽的酶、以及被检测物共存的步骤;测量在规定时间后的所述多肽的残留量的步骤;以及比较残留量的测量值与在不存在所述被检测物下测量的残留量的步骤。
序列号6是人肾上腺髓质素(AM)的全氨基酸序列。根据该筛选方法,可以得到能够期待改变具有序列号6所述的氨基酸序列等的多肽(AM等)的体内稳定性的物质。该物质具有能够提高 RAMP2参与的代谢综合症的治疗效果的可能性,可以期待作为代谢综合症的治疗药。另外,该方法中使用的酶在上述多肽中可以为特异性或非特异性,例如可以是肽链内切酶。
其它的筛选方法包括:使表达具有序列号1所述的碱基序列的DNA、具有能够在严紧条件下与序列号1所述的碱基序列杂交的碱基序列的DNA、或者由与序列号1所述的碱基序列具有90%以上的相同性的碱基序列构成的DNA、以及表达具有序列号4的DNA、具有能够在严紧条件下与序列号4所述的碱基序列杂交的碱基序列的DNA、或者由与序列号4所述的碱基序列具有90%以上的相同性的碱基序列构成的DNA的细胞与被检测物接触的步骤;以及检测基于具有序列号5所述的碱基序列的DNA所编码的配体的刺激的细胞内信号传导的诱导、或者基于所述配体的刺激的G蛋白质的活化的步骤。
序列号4是构成属于G蛋白偶联型受体class B的被称作CRLR(降钙素受体样受体)的七次跨膜型受体的氨基酸序列。并且,序列号5为人RAMP2基因的全碱基序列。
根据该筛选方法,可以得到在RAMP2和CRLR被一起表达的细胞中诱导基于AM刺激的细胞内信号传导、或者基于AM刺激活化G蛋白质的物质。该物质通过细胞内信号传导的诱导或G蛋白质的活化,具有能够提高基于RAMP2的代谢综合症治疗效果的可能性,可以期待作为代谢综合症的治疗药。
另外,以细胞内的cAMP、Ca、NO水平、PKA的活性水平、Akt、ERK、P38MAPK、P13K的磷酸化水平等的变化(尤其是上升)为指标,可以检测出细胞内信号传导的诱导。
其它的筛选方法包括:指定复合体所形成的结合口袋的立体结构的步骤、以及基于所述立体结构通过所述复合体和所述结合口袋由已知的结构文库在计算机上选择被预测为可结合的物质的步骤,其中所述复合体为具有在序列号2所述的氨基酸序列中将一个或多个氨基酸取代、缺失和/或插入后的氨基酸序列的多肽与具有在序列号5所述的氨基酸序列中将一个或多个氨基酸取代、缺失和/或插入后的氨基酸序列的多肽的复合体。
根据该筛选方法,能够将能结合在RAMP2和CRLR的复合体上的候选化合物由大量的物质大幅度减少。通过使用上述任意的筛选方法对减少后的候选化合物进一步进行限制,具有能够更加提高基于RAMP2的代谢综合症治疗效果的可能性,能够更进一步期待作为代谢综合症的治疗药。另外,该虚拟(in silico)筛选方法的步骤本身根据常规方法进行即可。
实施例
[试验例1]RAMP2基因敲除小鼠的制作
用以下步骤制作目标载体。即,在含有RAMP2的基因组DNA序列中,作为5’侧的相同序列,利用PCR合成含从RAMP2的外显子1的上游直到内含子1的途中的约3kb的序列(5’同源臂);作为中间的相同序列,利用PCR合成从内含子1的途中直到外显子4的下游(loxP臂);以及作为3’侧的相同序列,利用PCR合成外显子4的下游约3kb的序列(3’同源臂)。
然后,在pBluescript中,通过从5’侧到3’侧的方向以5’同源臂、loxP、loxP臂、新霉素抗性基因的序列(pGk-neo)、loxP、3’同源臂的顺序进行亚克隆,制作目标载体。即,设计为两个loxP位点夹着RMAP2的外显子2~4。
通过限制性内切酶处理使得到的目标载体成为线状后,用电穿孔导入到小鼠胚胎干细胞中。将新霉素抗性作为指标,对发生了重组的胚胎干细胞克隆进行浓缩,再通过DNA印迹杂交(Southernblotting)选择相同重组胚胎干细胞。
通过将选择的胚胎干细胞显微注射到小鼠囊胚中来制作嵌合小鼠。将该嵌合小鼠与野生型小鼠交配,制作在基因组序列的一个RAMP2基因的内含子1以及外显子4的下游插入有loxP位点的小鼠(杂flox小鼠)。
通过将制作的杂flox小鼠与在CAG启动子下将导入有表达Cre重组酶基因的基因的小鼠(CAG Cre小鼠)交配,得到由loxP夹着的区域被除去的RAMP2杂敲除小鼠。这些RAMP2杂敲除小鼠之间交配,得到RAMP2纯敲除小鼠。
[试验例2]与遗传性肥胖小鼠的交配
将在试验例1中得到的RAMP2杂敲除小鼠(RAMP2+/-)与作为遗传性肥胖的小鼠的瘦素缺乏(ob/ob)小鼠交配,通过使子代小鼠(RAMP2+/-、wt/ob)返回与ob/ob小鼠交配而制作孙代小鼠(RAMP2+/-、ob/ob)。
ob/ob小鼠呈现肥胖症状,RAMP2+/-、ob/ob小鼠呈现更重度的肥胖症状。其结果暗示了PAMP2的表达减少是肥胖症状恶化的原因。
[试验例3]脂肪肝
从ob/ob小鼠和RAMP2+/-、ob/ob小鼠提取肝脏,对其切片进行染色。由苏木素-伊红(HE)进行染色的照片如图1(a)所示,由油红O进行染色的照片如图1(b)所示。
如图1(a)所示,与ob/ob小鼠相比,在RAMP2+/-、ob/ob小鼠中在更广的范围内观察到可被看作脂肪滴的白色斑点。该结果也与图1(b)的结果一致,即,在图1(b)中,在RAMP2+/-、ob/ob小鼠中可以得到基于脂肪滴的染色的红色度比ob/ob小鼠强得多的图像。从这些结果可以显示出PAMP2的表达减少是脂肪肝症状恶化的原因。
[试验例3]动脉硬化
(形态学)
通过在通过试验例1得到的RAMP2杂敲除小鼠(RAMP2+/-)和野生型小鼠(RAMP2+/+)的大腿动脉周围留置聚乙烯管的涤纶套(cuff)四周时间来诱导由血管损伤带来的动脉硬化。用弹性vangieson染色对留置后的小鼠的大腿部涤纶套留置部的标本切片进行染色后的低倍率照片如图2(a)所示,大腿动脉部分的放大照片如图2(b)所示。
如图2(a)所示,RAMP2+/-小鼠与野生型小鼠相比,平滑肌的增殖、炎症细胞的浸润、细胞外基质的增生亢进。另外,如图2(b)所示,RAMP2+/-小鼠与野生型小鼠相比较,血管内腔侧观察到显著的新生内膜的形成。根据以上结果,RAMP2+/-小鼠与野生型小鼠相比,从形态学的观点考虑,可以判断动脉硬化症严重地恶化。
(免疫学)
为了在免疫学的观点上也确认图2的结果,研究了试验例3中的留置后的小鼠的大腿动脉中的ICAM1、VCAM1、MCP1以及PCNA蛋白质的表达量。具体地,使用结合在各蛋白质上的单克隆 抗体,通过常规方法对大腿动脉进行免疫染色,其结果如图3(a)~(d)所示。
如图3(a)~(d)所示,ICAM1、VCAM1、MCP1以及PCNA在RAMP2+/-小鼠中均比野生型小鼠具有显著多的表达量。
由于ICAM1和VCAM1是伴随着组织炎症而表达亢进的粘附因子,因此,暗示了在RAMP2+/-小鼠中产生比野生型小鼠更强的炎症。该暗示可以由作为趋化因子的MCP1的表达在RAMP2+/-小鼠中比在野生型小鼠中亢进得到证明。
另外,由于PCNA为增殖细胞的标志,因此可以确认平滑肌的增殖在RAMP2+/-小鼠中比在野生型小鼠中亢进。
图3(f)是留置后的小鼠的大腿动脉切片的二氢乙啶(DHE)染色图,图3(e)是由p67phox抗体进行的大腿动脉切片的免疫染色图。
如图3(f)所示,在RAMP2+/-小鼠中比在野生型小鼠中能够范围广得多且强得多地观察到表示超氧化物的存在的红色的染色。由此可以确认在病变部的氧化应激在RAMP2+/-小鼠中比在野生型小鼠中亢进。
另一方面,如图3(e)所示,p67phox在RAMP2+/-小鼠中比野生型小鼠具有显著多的表达量。根据p67phox是与产生活性氧相关的NADPH氧化酶的亚基,暗示了NADPH氧化酶活性的亢进成为在病变部的氧化应激的亢进的原因。
根据以上结果,RAMP2+/-小鼠与野生型小鼠相比,从免疫学的观点考虑,可以判断动脉硬化症严重地恶化。
(分子遗传学)
对所述留置前后的小鼠了考察了RAMP2、RAMP3、CRLR以及AM的表达量。即,从留置前后的小鼠提取大腿动脉附近的组织,以由该组织提取的全RNA为模板,使用各基因特异的序列的引物进行定量实时PCR。具体的步骤依据常规方法。其结果如图4所示。
如图4所示,PAMP2+/-小鼠与野生型小鼠相比,留置前后的PAMP2的表达量有意义地降低,另外,PAMP3和CRLR的表达量在统计上等同。由此,试验例3中表示的结果显示了在PAMP2+/-小鼠中的动脉硬化症与野生型小鼠相比恶化,这暗示了PAMP2的表达量低。
另外,在损伤前的状态,AM的表达在PAMP2+/-小鼠中亢进。这暗示了即使在成体中,如果RAMP2表达量降低,则作为配体的AM的表达也会随着正反馈而上升。换言之,不仅胎生期血管,即使在成体的血管中,RAMP2也显示出传导AM信号的中心作用。
损伤后AM的表达量在野生型和RAMP2+/-小鼠之间无有意义的差,这可以认为因为是即使是野生型在损伤后也引起AM的表达亢进。而且,在RAMP2+/-小鼠中,尽管在本底信号中的AM的表达量亢进(或者尽管在损伤后与野生型小鼠的AM表达量之间无有意义的差),但是动脉硬化在RAMP2+/-小鼠中仍为重度,这可以认为是因为即使AM表达亢进,但是由于RAMP2表达量低,所以由AM带来的抗动脉硬化作用不能充分发挥。从以上的机制可以推测仅AM表达量亢进不能发挥抗动脉硬化作用,只有使RAMP2表达量亢进才能够发挥抗动脉硬化作用。
[试验例4]血管闭塞
(形态学)
在通过试验例1而得到的RAMP2杂敲除小鼠(RAMP2+/-)和野生型小鼠(RAMP2+/+)的大腿动脉周围涂布10%氯化铁溶液,涂布24小时后提取各小鼠的大腿部。其切片的HE染色照片如图5所示。另外,利用提取的大腿动脉的横切片(n=5)来对血栓的横截面积进行定量。而且基于血栓的横截面积和血管内腔的全面积的比来计算血管的狭窄率。血栓大小如图6所示,血管的狭窄率如图7所示。
如图5所示,RAMP2+/-小鼠与野生型小鼠相比,观察到大的血栓的存在。该结果与RAMP2+/-小鼠的血栓量(图6)和血管的狭窄率(图7)有意义地高于野生型小鼠一致。这些结果暗示了从形态学的观点考虑,RAMP2表达的降低使血栓症恶化,促进了血管闭塞。
(免疫学)
考察了试验例4中的大腿动脉的MCP-1和Mac-1蛋白质的表达量。具体地,使用结合在各蛋白质上的抗体根据常规方法对大腿动脉进行免疫染色,其结果如图8所示。
如图8所示,MCP-1和Mac-1蛋白质在RAMP2+/-小鼠中均比野生型小鼠具有更大范围的表达量。由于MCP-1和Mac-1蛋白质是伴随着组织炎症而表达亢进的趋化因子和粘附因子,因此暗示了RAMP2+/-小鼠在闭塞部位产生比野生型小鼠更强的炎症。
[试验例5]条件性打靶
为了解释AM-RAMP2系统的病理生理学意义,需要RAMP2敲除小鼠的纯合子,但是纯合子(RAMP2-/-)是胎生致死。因此,使用Cre-loxP系统进行RAMP2基因的条件性打靶,使RAMP2各细胞系列特异性地缺失。
(血管内皮细胞)
具体地根据常规方法建立用Flox序列夹着RAMP2基因座的loxP小鼠。另一方面,建立导入有血管内皮细胞特异性表达的血管内皮钙粘附素(Cdh5)的启动子序列位于Cre序列的5’侧的载体(参照图9,Circulation Research.2006;98:897-904)的Cre小鼠。通过使loxP小鼠和Cre小鼠交配,得到RAMP2被血管内皮细胞特异性地敲除的小鼠。
将建立的8~10周龄的成体小鼠麻醉后开腹,用含胶原酶的培养液对肝脏内进行灌流,原代培养分离培养后的窦状(類洞)内皮细胞。将由该细胞提取的全RNA逆转录为cDNA,使用具有特异性序列的引物对RAMP2进行定量实时PCR。其结果,如图10所示,确认了血管特异性RAMP2敲除小鼠与野生型小鼠相比只表达了远远少量(约20%)的RAMP2。
另外,从血管特异性RAMP2敲除小鼠和野生型小鼠中提取肺,该肺的切片的HE染色照片如图11所示。如图11(a)所示,在敲除小鼠中观察到了较大的炎症(图11(a)中、被圆包围的部分),如作为图11(a)的局部放大图的图11(b)所示,也可以确认敲除小鼠与野生型小鼠相比炎症为重度。
然后,从血管特异性RAMP2敲除小鼠和野生型小鼠中提取肾脏,该肾脏的外观照片如图12(a)所示,截面照片如图12(b)所示,切片的HE染色照片如图12(c)所示,图12(c)的局部放 大图如图13所示。敲除小鼠与野生型小鼠相比,全体膨胀(参照图12(a)),确认了肾小球硬化症、大疱(bullae)的形成、肾积水症等肾功能障碍(参照图12(b)、(c)、图13)。
根据图10~13的结果,暗示了RAMP2表达量的降低在各个器官中促进了损伤。
(心肌细胞)
建立导入有心肌细胞特异性表达的α-MHC的启动子序列位于Cre序列的5’侧、且结合他莫昔芬的变异型雌激素受体(Mer)序列位于Cre的两侧的载体(参照图14、Circ Res.2001;89;20-25.)的Cre小鼠。除了使用该Cre小鼠这点不同外,按照与上述同样的步骤,得到RAMP2被心肌细胞特异性敲除的小鼠。
向建立的小鼠腹腔内给与他莫昔芬30mg/kg/日,开始给药一周后提取心脏。该心脏的外观照片如图15(a)所示,切片的Masson三色染色照片如图15(b)所示。另外,利用心脏的横截组织切片测量心肌细胞的横径的结果如图17所示。如图15(a)、(b)所示,确认了RAMP2心肌细胞特异性敲除小鼠与野生型小鼠相比,心脏肥大,该心脏肥大伴随着心肌细胞的肥大(图17)。推测这些症状起因于RAMP2表达量的降低。
图16示出了图15(b)的局部放大图。如图16所示,在RAMP2心肌细胞特异敲除小鼠中观察到纤维化硬化的病变部较多,另外,野生型小鼠未观察到病变部位。推测这样的心脏的纤维化起因于RAMP2表达量的降低。
工业上利用的可能性
以上结果显示了AM的多样的生理作用由RAMP2来规定,换言之,通过将RAMP2作为靶标,可以人为地操作AM的生理作用,可以总括地治疗或预防代谢综合征。由于RAMP2是低分子一次跨膜型蛋白质,所以不仅血中半衰期长,在体内的稳定性良好,而且其结构解析、可以人为控制该系统的低分子化合物激动剂的探索等也比较容易。因此RAMP2极其有望作为治疗靶标分子。
序列表
<110>独立行政法人科学技术与振兴机构
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Claims (2)
1.编码受体活性修饰蛋白(RAMP)2的以下(a)所述的DNA、或者该DNA编码的多肽作为有效成分在制备代谢综合症的治疗或预防剂中的应用,
(a)具有序列号1所述的碱基序列的DNA,
所述代谢综合症为内脏脂肪型肥胖与高血糖、高血压以及高血脂中的两种以上并发的复合生活习惯病。
2.能够特异性扩增由序列号3所述的碱基序列构成的DNA的引物、或者与由序列号2所述的氨基酸序列构成的多肽特异性结合的抗体作为有效成分在制备代谢综合症的检查药中的应用,所述代谢综合症为内脏脂肪型肥胖与高血糖、高血压以及高血脂中的两种以上并发的复合生活习惯病。
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US4248853A (en) * | 1978-09-08 | 1981-02-03 | Solomon Halbert Snyder | Assay method and kit |
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EP2221065B1 (en) | 2016-12-28 |
EP2221065A4 (en) | 2011-05-11 |
JPWO2009069546A1 (ja) | 2011-04-14 |
WO2009069546A1 (ja) | 2009-06-04 |
EP2221065A1 (en) | 2010-08-25 |
JP5099856B2 (ja) | 2012-12-19 |
CN101873866A (zh) | 2010-10-27 |
US8858915B2 (en) | 2014-10-14 |
US20110027187A1 (en) | 2011-02-03 |
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