CN1863548A - 治疗细胞外基质紊乱的方法和组合物 - Google Patents
治疗细胞外基质紊乱的方法和组合物 Download PDFInfo
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Abstract
本发明提供一种改变细胞产生的细胞外基质水平的方法,该方法包括调节细胞分裂自身抗原(CDA)的表达或活性。申请人惊奇的发现,CDA参与哺乳动物细胞产生的ECM蛋白水平的控制途径。本发明涉及多种ECM相关紊乱,例如肾脏纤维化和动脉粥样硬化。
Description
本发明涉及结缔组织生物学领域。更具体地,本发明涉及治疗细胞外基质(extracellular matrix,ECM)相关的结缔组织紊乱,例如纤维化,和继发性疾病,例如肾脏疾病,糖尿病和动脉粥样硬化。
前言
ECM是一种胶样物质,通常在结缔组织中具有结构功能。ECM由基质和纤维组成。基质是无定形物质,其填充间质组织,由组织液,细胞吸附蛋白和蛋白聚糖组成。细胞吸附蛋白使得结缔组织细胞附着到基质元件上。蛋白聚糖能保持水份,从而形成半硬水合胶。
多聚糖的相关数量和种类有助于决定基质的性能。例如,多聚糖数量越多,基质越硬。基质支撑细胞,将其连接在一起,并作为一种介质,通过该介质,营养成分和其他溶解物质能在毛细血管和细胞之间扩散。
基质中的纤维提供强度。结缔组织基质中发现三种纤维:胶原,弹性和网状纤维。胶原纤维(白纤维)极为强韧,提供高抗张强度,该强度是抵抗纵向应力的能力。由于新鲜胶原纤维具有闪亮的白色外观,该纤维有时也被称之为“白纤维”。弹性纤维(黄纤维)能伸展到原长度的1-1.5倍,但松解后又能回缩到初始长度。在需要更大弹性的组织中能发现他们,例如肺,血管壁。新鲜的弹性纤维外观呈黄色,也称之为黄纤维。网状纤维是一种纤细成胶纤维。该纤维形成精巧分枝状的网状物,支撑着柔软器官,例如肝脏和脾脏。
虽然ECM在机体内明显地起到重要的结构功能,但ECM紊乱也是常见和严重的。纤维化是在动物体中源于ECM超量产生导致瘢痕组织产生的普通术语。已经证实,在美国,45%的死亡归因于纤维增生紊乱。
纤维化可能源于多种原因,包括外伤,手术,感染,环境污染,酒精和其它类毒素。有多种纤维化的实例,包括心脏病发作后的瘢痕组织形成,结果损伤心脏泵功能。糖尿病经常引起肾脏损伤和瘢痕形成,结果导致肾功能进行性损伤。甚至手术后,瘢痕组织能在内部器官之间形成,从而引起挛缩、疼痛,在某些情况下还引起不孕。
尽管纤维化紊乱可以是急性或者慢性的,但都具有相同的特征:过度胶原聚集,和正常组织被瘢痕组织代替后,出现相关功能丧失。
急性纤维化(通常伴随突然和严重的发作和短期持续)作为各种外伤形式的共同反应而发生,所述外伤包括事故损伤、感染、手术、烧伤、放射和化疗治疗。所有外伤损伤组织都倾向于瘢痕化且变为纤维化,尤其是反复损伤时。
慢性纤维化可源于病毒感染、糖尿病、高血压和其他慢性状况诱导进行性纤维化,结果引起组织功能持续丧失。影响最普遍的是肝脏、肾脏和肺。深度器官纤维化常常是极为严重的,因为器官功能进行性丧失导致发病、住院治疗、透析、残疾和甚至死亡。
尽管ECM紊乱广泛普遍存在,使人衰弱,且经常威胁生命,但目前没有有效的治疗。由于这种ECM相关紊乱的多种形式的不利临床反应,显然需要有效的治疗。
申请人克服或减轻了现有技术中的问题,发现一种已知细胞蛋白参与ECM紊乱的病理生理过程。
发明概述
本发明一方面提供一种改变细胞产生的细胞外基质(ECM)蛋白水平的方法,所述方法包括调节细胞分裂自身抗原(cell division autoantigen,CDA)的表达或活性。申请人惊奇地发现,CDA参与哺乳动物细胞产生的ECM蛋白水平的控制途径。本发明涉及多种ECM相关紊乱,例如肾脏纤维化和动脉粥样硬化。
CDA可以是细胞分裂自身抗原1(CDA1),或其功能等同物或衍生物。
本发明另一方面提供一种治疗或预防ECM蛋白合成相关状况的方法,所述方法包括调节CDA的表达和/或活性。
本发明还提供一种非-人动物,用于研究ECM紊乱,所述动物包含以改变水平表达CDA1的细胞。
本发明另一方面提供一种筛选能调节ECM合成的试剂的方法,该方法包括以下步骤:
提供能表达CDA1的动物或者细胞,
将所述动物或者细胞暴露到试剂中,和
测定试剂对CDA1表达和/或活性的影响。
本发明进一步包括通过本发明的筛选方法鉴定的试剂,以及包括该试剂的药物组合物。
本发明进一步包括一种治疗或预防ECM相关状况的方法,该方法包括对需要所述治疗或预防的动物施予有效量的本发明的药物组合物。
本发明还提供一种调节细胞中CDA1表达和/或活性的方法,该方法包括将细胞暴露在能调节下列因子活性的试剂中,所述因子选自血管紧张素II,TGFβ和结缔组织生长因子。
本发明还进一步提供一种诊断ECM蛋白合成相关状况的方法,所述方法包括
从动物体中获得生物样本,
测定样本中的CDA1水平,和
比较样本中的CDA1水平和参考值
其中,样本中的CDA1水平统计学意义上显著高于或低于参考值时,诊断为阳性。
附图说明
附图1显示远端小管和集合管中的CDA1表达。该部分(sections)用HE对染(核染为蓝色)。板A:人组织。板B:大鼠肾脏组织。
附图2显示响应于体内Ang II刺激,肾脏内CDA1表达增高。板A:CDA1表达对照。板B:暴露于血管紧张素II后的CDA1表达。板C:暴露于血管紧张素II后的TGFβ1表达。图D:暴露于血管紧张素II后的TGFβ2表达。
附图3显示肾脏质量减少后CDA1表达和纤维化增加。该部分用HE对染(核染为蓝色)。板A:次全部肾切除术时的CDA1表达。板B:暴露于缬沙坦(valsartan)后次全部肾切除术时的CDA1表达。
附图4显示近端小管细胞(proximal tubule cells)中CDA1过表达和细胞外基质蛋白产生。板A:在载体转染的NRK细胞中的胶原IV染色。板B:在CDA1转染的NRK细胞中的胶原IV染色。板C:在载体转染的NRK细胞中的纤连蛋白染色。板D:在CDA1转染的NRK细胞中的纤连蛋白染色。
附图5显示糖尿病大鼠肾脏中的CDA1表达。该部分用HE对染(核染为蓝色)。板A:对照肾脏中的CDA1表达。板B:8周时的CDA1表达。板C:32周时的CDA1表达。
附图6显示动脉粥样硬化斑块中的CDA1表达。CDA1染色为棕色,核染色为蓝色。板A:非糖尿病小鼠动脉。板B:糖尿病(apoE)小鼠动脉。
附图7显示编码人CDA1的DNA序列。
附图8显示人CDA1蛋白质序列。
发明详述
一方面,本发明提供一种改变细胞产生的细胞外基质(ECM)蛋白水平的方法,所述方法包括调节细胞分裂自身抗原(CDA)的表达或活性。申请人惊奇地发现,CDA参与控制哺乳动物细胞产生的ECM蛋白水平的途径。
ECM是一种复杂结构实体,围绕并支撑着哺乳动物组织中的细胞。ECM经常被认为是结缔组织。ECM由三个主要的生物分子类别组成:结构蛋白(胶原和弹性蛋白),特化蛋白(原纤蛋白,纤连蛋白,和层粘连蛋白)和蛋白聚糖。
因此,本发明的优选ECM蛋白选自胶原,弹性蛋白,原纤蛋白,纤连蛋白,层粘连蛋白和蛋白聚糖。更为优选,ECM蛋白为纤连蛋白或胶原IV。
本发明中,术语“调节CDA的表达或活性”是指和非更改水平比较,更改或改变CDA的表达和/或活性。调节表达可以包括诱导或增加表达和/或活性或者减少表达和/或活性。
细胞中CDA的表达和/或活性的调节可通过使用CDA拮抗剂、抑制剂、模拟物或衍生物而获得。本发明的术语“拮抗剂”或“抑制剂”是指阻滞或调节CDA生物活性的试剂。拮抗剂和抑制剂蛋白,核酸,碳水化合物,抗体或其他任何分子或配体。蛋白可以包括酶,该酶能降解CDA,因而影响细胞内外的CDA水平。其他CDA活性和/或表达调节剂包括一些合理设计的,合成的抑制剂。
CDA的表达和/或活性的调节可通过直接或间接方法而获得。通过本领域技术人员公知的直接方法可以获得CDA的表达和/或活性的调节,所述方法包括但不仅限于,敲除技术,反义技术,三链螺旋(triplehelix)技术,靶向突变,基因治疗,作用于转录的试剂调节。CDA的表达和/或活性的调节的间接方法包括但不仅限于,靶向上游或下游调节子,例如细胞因子。
术语“活性”涉及CDA在细胞中的功能,包括CDA结合到陪伴分子,上游或下游效应分子的能力,因而活化或抑制影响ECM蛋白产生的上游或下游途径。
优选地,细胞来源于肾脏组织或血管组织。以前没有报道肾脏中CDA1表达。申请人的研究显示,CDA1在包括末端小管(distaltubules)和集合管(参见附图4)的肾脏中表达。CDA1在正常大鼠的末端小管和集合管的表达证实了细胞质和细胞核模式。CDA1很少在正常大鼠肾的肾小球中表达。
更为优选地,细胞选自肾足细胞,肾近端小管细胞,肾集合管细胞,泡沫细胞或巨噬细胞。
也观察到次全部肾切除术(STNx)后残留肾中的CDA1表达和纤维化的共定位(附图3)。肾重量减少后,在肾小球内的足细胞中出现了CDA1表达(附图6A),但该表达在正常肾中没有。细胞质和核染色模式很明显,尤其是在硬化肾小球中和小管间质性纤维化位点上。我们的初期资料也提示,阻滞血管紧张素II例如AT1受体拮抗剂-缬沙坦的治疗方法和更少的细胞损伤和CDA1表达衰减关联(附图3B)。
用现有技术公开的相同的CDA1转染技术(Chai等人,(2001)SET-related Cell Division Autoantigen-1(CDA1) Arrests Cell Growth.J.Biol.Chem.276:33665-33674,以下引用为“Chai等人,2001”)。申请人将CDA1转染到近端小管细胞系,NRK-52E。我们的初步研究表明,和只转染载体的细胞(附图4A和4C)相比,CDA1转染细胞中产生的包括胶原IV(附图4B)和纤连蛋白(附图4D)的基质蛋白增加。该结果提示CDA1可能直接关系到细胞外基质的产生和随后的肾纤维化进展。
本发明的CDA的优选形式是细胞分裂自身抗原1(CDA1),或其片段,功能等价物,类似物,或突变体或变体。
CDA1是最近用盘形红斑狼疮患者的血清鉴定出的新的核蛋白,申请人以前详细公开了CDA1的分子克隆和结构(参见PCT/AU01/0148,公开号WO02/36768)。简而言之,CDA1的cDNA有2808个碱基对,其2079个碱基对的开放性阅读框编码推测的693个氨基酸的多肽,命名为CDA1。CDA1推测的分子量为79,430道尔顿,pI为4.26。
CDA1包括N-端脯氨酸富集区,中心碱性区(basic domain)和C-端双酸区。申请人最初的研究证实,CDA1包含四个推定的核定位信号,cAMP和cGMP依赖性激酶,蛋白激酶C,胸苷激酶,酪蛋白激酶II,细胞周期蛋白依赖性激酶(CDKs)的磷酸化潜在位点。CDA1在HeLa细胞中磷酸化,体外经细胞周期蛋白D1/CDK4,细胞周期蛋白A/CDK2和细胞周期蛋白B/CDK1磷酸化。CDA1的碱性和酸性区包含与几乎完整的人白血病相关SET蛋白同源的区域。
CDA1表达在细胞周期中是动态的,其表达水平和细胞周期的不同期和培养条件直接相关。血清饥饿细胞(G0期)中,CDA1表达水平非常低。将血清加到培养基中刺激细胞周期(G1期)和CDA1表达增高关联。加入2mM胸苷到培养基中阻滞细胞在G1/S,CDA1表达达到高峰。加入0.15μg/ml秋水仙酰胺使细胞停止在M期,CDA1表达下降,但比G0期高。
其他研究随后鉴定出CDA1,并证实CDA1是TGFβ1靶基因,命名为差异表达核仁TGF-β1靶点(differentially expressed nucleolarTGF-β1target,DENTT)。已经证实,体外TGFβ1使CDA1表达增加。CDA1(也称为DENTT)在脑垂体中高表达,在肾上腺,脑,胰岛,睾丸和卵巢中中等表达,提示在内分泌器官中该蛋白的优势。
更为优选地,CDA1由附图7所示的核苷酸序列或编码其功能等价物或衍生物的序列编码。CDA1可以包含如附图8所示的氨基酸序列或其功能等价物或衍生物。
本发明的术语“功能等价物或衍生物”包括但不仅限于片段,所述片段具有CDA1的功能活性,或其同源物,类似物,突变体,变体和衍生物。这包括来自天然、重组或合成来源包括融合蛋白的同源物,类似物,突变体,变体和衍生物。述及“同源物”应当理解为,述及来源于其他物种,而不是被处理的物种的CDA1核酸分子或蛋白质。
衍生物包括来自天然、合成或重组来源包括融合蛋白的片段,部分,部份,突变体,变体和模拟物。部分或者片段包括,例如CDA1的活性区。衍生物可以来自氨基酸的插入,缺失或取代。氨基酸插入衍生物包括氨基和/或羧基端融合,以及单个或多个氨基酸段内序列插入。插入氨基酸序列变体是指那些一个或多个氨基酸残基被引入到蛋白质预定位点的变体,尽管,用合适的终产品筛选方法随机插入也是有可能的。缺失变体的特征在于序列中去除一个或多个氨基酸。取代氨基酸变体是指那些序列中至少一个残基被去除,在其位置上插入了不同的残基。一个取代氨基酸变体的实例是保守氨基酸取代。典型的保守氨基酸取代包括下列组的取代:甘氨酸和丙氨酸;缬氨酸,异亮氨酸和亮氨酸;天冬氨酸和谷氨酸;天冬酰胺和谷氨酰胺;丝氨酸和苏氨酸;赖氨酸和精氨酸;苯丙氨酸和酪氨酸。添加到氨基酸序列包括和其他肽,多肽或蛋白融合。
应当理解,CDA1核酸或蛋白分子的化学和功能等价物包括表现上述分子的任意一种或多种功能活性的分子,并且可以是任何来源,例如化学合成或通过筛选方法,例如天然产品筛选鉴定的分子。
衍生物包括具有完整蛋白的特定表位或部分的片段,所述完整蛋白融合到肽,多肽,其他蛋白质或非蛋白质分子中。
本发明预期的(contemplated)类似物包括,但不仅限于,侧链修饰,在肽、多肽或蛋白质合成时的非天然氨基酸和/或其衍生物的引入和使用交联剂和其他给蛋白质分子或其类似物施加构象限制的方法。
相似的,核酸序列的衍生物可以来源于单个或多个核苷酸取代、缺失和/或添加,包括和其他核酸分子融合。本发明的核酸分子衍生物包括寡核苷酸,PCR引物,反义分子,适合用于核酸分子共抑制和融合的分子。核酸序列衍生物还包括简并变体。
本发明预期的侧链修饰实例包括氨基修饰,例如通过氨基和醛反应的还原烷基化,然后在NaBH4下还原,与亚氨逐乙酸甲酯(methylacetimidate)脒化;和乙酸酐反应酰化;和氰酸酯反应的氨基的甲酰化;和2,4,6-三硝基苯磺酸(TNBS)反应的氨基的三硝基苄基化;和琥珀酸酐和四氢化邻苯二甲酸酐反应的氨基的酰化;与吡哆醛-5-磷酸反应的赖氨酸的吡哆酸化(pyridoxylation),然后NaBH4还原。
精氨酸残基的胍基可以通过和试剂,例如2,3丁二酮,苯甲酰甲醛和乙二醛反应形成杂环缩合产物进行修饰。
羧基修饰可以是通过形成O-酰基异脲的碳二亚胺活化,然后衍生为,例如相应的酰胺。
巯基的修饰方法可以是:例如,和碘乙酸或碘乙酰胺反应的羧甲基化;过甲酸氧化为磺丙氨酸;与其他硫醇化合物形成混合的二硫化物,和马来酰亚胺,马来酸酐或其他取代的马来酰亚胺反应;利用4-氯汞基苯甲酸酯(4-chloromercuribenzoate),4-氯汞基苯磺酸,苯汞基氯,2-氯汞基-4-硝基苯酚和其他汞制剂形成汞衍生物,在碱性pH下和氰酸酯的氨甲酰化。
色氨酸残基的修饰可以是,通过例如,用N-溴基琥珀酰亚胺进行的氧化;或用2-羟基-5-硝基苄基溴或者磺苯卤化物(sulphenylhalides)反应使得吲哚环烷基化。另一方面,酪氨酸残基可通过用四硝基甲烷硝化形成3-硝基酪氨酸衍生物而改变。
组氨酸残基的咪唑环的修饰可以通过和碘乙酸衍生物发生烷基化反应或者和焦碳酸二乙酯发生N-羰基乙氧基化(N-carboethoxylation)来实现。
在蛋白合成中引入非天然氨基酸和衍生物的实例包括,但不仅限于使用正亮氨酸,4-氨基丁酸,4-氨基-3-羟基-5-苯戊酸,6-氨基己酸,叔-丁基甘氨酸,正缬氨酸,苯基甘氨酸,鸟氨酸,肌氨酸,4-氨基-3-羟基-6-甲基庚酸,2-噻吩基丙氨酸和/或氨基酸的D型异构体。
本发明的另一方面提供一种治疗或预防ECM蛋白合成相关状况的方法,该方法包括调节CDA的表达和/或活性。
ECM蛋白合成相关状况包括纤维化,所述纤维化源于外伤,尤其是脊柱和中枢神经系统损伤。还包括烧伤,其他肥大瘢痕,心脏病发作后的心脏瘢痕,血疗法药物诱导的纤维化,放射诱导的纤维化,肺纤维化(急性呼吸窘迫综合征)和手术瘢痕。
状况可以是主要器官纤维化,包括肾疾病(例如,由于糖尿病或高血压),肝脏纤维化(例如,由于病毒性肝炎或酒精滥用),肺纤维化,心脏纤维化,黄斑变性、视网膜和玻璃体视网膜病变。
状况也可以是紊乱,例如全身和局部硬皮病、瘢痕瘤、肥大瘢痕、动脉粥样硬化或再狭窄。
更优选的,本发明的状况是糖尿病引起的肾脏纤维化。申请人发现,8周龄糖尿病大鼠的CDA1表达增加(附图6)。而且,糖尿病诱导后32周,肾脏CDA1表达进一步增加。CDA1表达增加还发现于肾小管和间质组织中。
尤其有趣的是,在糖尿病大鼠的足细胞(podocytes)中从头(denovo)表达CDA1,而在正常大鼠的肾脏中没有表达(附图2)。申请人证实,在糖尿病肾病中足细胞发生损伤,裂孔隔膜蛋白例如肾升压素(nephrin)表达不足可能部分对糖尿病中的蛋白尿负责。基于这些CDA1相关资料和已知的糖尿病肾病的病理生理学知识,申请人认为,这种新蛋白是糖尿病肾病的功能和结构临床表现之间的重要连接。
不希望受理论限制,认为在糖尿病中通过血管紧张素II、TGFβ和CTGF活化的血液动力学和代谢途径,增加CDA1表达,因而增加ECM蛋白例如纤连蛋白和胶原IV的产生。
本发明进一步优选的实施方案中,所述状况是动脉粥样硬化。申请人研究显示,在糖尿病ApoE敲除小鼠的动脉的动脉粥样硬化斑块中,CDA1染色增加(附图6),提示CDA1可能在动脉粥样硬化的进展中起作用。动脉粥样硬化是动脉的常见紊乱。脂肪、胆固醇和其他物质在动脉壁聚集并形成“粉瘤”或斑块。最终脂肪组织可腐蚀动脉管壁,减少动脉弹性和影响血流。
血凝块可以在斑块沉积四周形成,进一步干扰血流。当动脉到心肌的血流变得严重受阻时,心肌损害就不可避免。
风险因素包括吸烟,糖尿病,肥胖,高血压,高血胆固醇,高脂肪饮食,具有心脏病个人或家庭史。脑血管疾病,外周血管疾病和涉及透析的肾脏疾病也是可能和动脉粥样硬化关连的紊乱。本发明预期治疗或预防动脉粥样硬化。
本方法还可用于治疗某些状况,在所述状况中,ECM蛋白的增加是令人期望的,例如动脉瘤,更具体而言是腹部动脉的动脉瘤。
本发明还提供一种用于研究ECM紊乱的非-人动物,所述动物包含能以改变的水平表达CDA1的细胞。所述动物可以是“敲除”动物,根本不表达CDA1。所述动物可以表达具有下降活性的CDA1。预期这种动物将用作研究ECM相关状况或筛选试剂的模型,所述试剂用于任何ECM相关状况的治疗或预防。
本发明的另一方面提供一种筛选能调节ECM合成的试剂的方法,所述方法包括下列步骤:
提供能表达CDA1的动物或者细胞,
将所述动物或者细胞暴露到所述试剂中,和
测定试剂对CDA1表达和/或活性的影响。
本发明进一步包括通过本文所述的筛选方法鉴定的试剂以及包括用于治疗ECM相关疾病的药物组合物。制备药物和化妆品组合物的方法和载体在现有技术中是众所周知的,如教科书所述(例如Remington’s Pharmaceutical Sciences,第18版,Mack PublishingCompany,Easton’Pennsylvania,USA),其中的内容在此引入。
药物组合物可以以治疗或预防ECM相关状况的治疗或预防有效量施予。此处的术语“治疗或预防有效量”含义是指下列效果的必需量:至少部分获得预期的效果,或者延迟发作,抑制进展,或完全停止ECM相关状况的发作或进展。当然,这些量可依赖于具体治疗的状况,状况的严重性,和个体参数,包括年龄,生理状态,身材,体重和其他并行的治疗。这些因素对于本领域技术人员来说是熟知的,只要常规试验就能确定。一般优选地,最小有效剂量可根据合理的医学或治疗判断确定。然而,本领域普通技术人员可以理解,由于医疗或其他原因可以用更高的剂量。技术人员对适用于本发明的一系列给药途径和剂量方案也熟悉。对于一个特定的临床应用,只要用常规的试验就能确定最佳的制剂,给药途径或剂量方案。
本发明进一步包括治疗或预防ECM相关状况的方法,所述方法包括对需要所述治疗或预防的动物施予本发明公开的有效量的药物组合物。所述ECM相关状况是上文描述的任何状况。
本发明还提供一种调节细胞中CDA1表达和/或活性的方法,所述方法包括暴露细胞到能调节下列因子活性的试剂中,所述因子选自血管紧张素II,TGFβ和结缔组织生长因子。
申请人显示,注入血管紧张素II后,CDA1表达增加(附图5B)。CDA1免疫组织化学染色显示,近端小管的细胞质和细胞核染色水平都增加。血管紧张素II注入后的CDA1表达增加可以通过缬沙坦(valsartan),一种AT1受体拮抗剂处理来防止(资料未显示)。
血管紧张素II注入后CDA1表达增加的小管(tubular)模式(附图5B)和TGFβ(附图2C)和TGFβ2(附图2D)相似。而且,观察到增加的近端小管CDA1表达的位点和两个重要原细胞凋亡蛋白p53和bax增加的表达的位点相同(资料未显示)。p53和bax的共表达和CDA1参与到细胞增殖的抑制相一致。
本发明还提供一种诊断ECM蛋白合成相关状况的方法,所述方法包括
从动物体中获得生物样本,
测定该样本中的CDA1水平,和
比较该样本中的CDA1水平和参考值
其中,如果该样本中的CDA1水平统计学意义上显著高于或低于参考值时,诊断为阳性。
所述方法预期用于诊断本发明公开的与ECF异常相关的任何疾病。
实施例
实施例1:CDA1表达和Ang II:时间和剂量关系
8周龄雄性SD(Sprague Dawley)大鼠,皮下嵌入微泵持续注入Ang II3或14天,剂量为升压剂量(pressor doses)(60ng/min)和非升压剂量(6ng/min)(Cao等人,Z;The angiotensin type 2receptoris expressed in adult rat kidney and promotes cellular proliferation andapoptosis.Kidney Int.2000;58:2437-2451)。结果如附图2所示。
实施例2:残留肾脏中的CDA1表达和纤维化
通过右肾切除术进行次全部肾切除术(subtotal nephrectomy)(STNx),随后,除了左肾动脉的一个肾外分支外选择性结扎其他所有动脉使得大约2/3左肾梗塞(CIA40)。腹膜内注射戊巴比妥钠(60mg/kg)进行麻醉。假手术大鼠作为对照。手术后,大鼠分别在1,2,4,8和12周处死,收集组织,用于检测CDA1表达,纤维化生长因子以及基质蛋白。结果如附图3所示。
实施例3:存在或缺乏AngII、TGFβ和CTGF刺激下,CDA1过表达对胶原、骨桥蛋白、纤连蛋白表达的影响
通过CDA1转染培养的正常大鼠肾脏上皮细胞系得到CDA1过表达。通过CDA1转染培养的正常大鼠肾脏上皮细胞系(NRK52E)得到CDA1过表达。使用表达Myc-标记CDA1的构建体,即CDNA3-2M-CDA1,和pCDNA3-2M载体对照DNA,通过前述的转染Hela细胞的电穿孔方法(参见Chai,等,2001)转染NRK52E细胞。
转染细胞平铺到盖玻片上,用没有胎牛血清的DMEM培养3天。免疫组织化学检测纤连蛋白和其他基质蛋白。可以用下述引用文献中的方法,用实时RT-PCR或免疫化学检测TGFβ、胶原I、和纤连蛋白的基因表达:Cao等,Blockade of the renin angiotensin andendothelin systems on progressive renal injury.Hypertension 2000;36:561-568;Twigg等Renal connective tissue growth factor induction inexperimental diabetes is prevented by aminoguanidine.Endocrinology.2002;143:4909-4913。
存在或缺乏CDA1或载体转染细胞的细胞外基质蛋白用免疫组织化学检测。结果如附图4所示。
8周龄SD大鼠通过静脉内注射链脲霉素(STZ)诱导糖尿病(Allen等Role of angiotensin II and bradykinin in experimental diabeticnephropathy-functional and structural studies.Diabetes.1997;46:1612-1618)。动物在糖尿病8和32周后处死,摘取肾脏,用于随后免疫组织化学检测CDA1。结果如附图5所示。
在ApoE敲除小鼠中诱导STZ糖尿病(每天一次STZ,注射6天),糖尿病20周后,摘取动脉,用于免疫组织化学检测。结果如附图6所示。
实施例4:CDA1免疫组织化学方法
在石蜡包埋部分(sections)用兔抗人CDA1血清进行CDA1染色(chai等,2001)。简而言之,脱蜡后,石蜡包埋部分在微波炉中用低火在10mmol/L柠檬酸钠缓冲液(pH=6.0)中处理10分钟。用3%双氧水(H2O2)甲醇溶液作用20分钟失活内源性过氧化物酶。该部分用蛋白封闭试剂封闭20分钟。然后将其和兔抗人CDA1血清室温孵育2小时。用生物素化山羊抗兔免疫球蛋白(DAKO A/S)作为第二抗体,随后用抗生物素蛋白生物素辣根过氧化物酶复合物(ABC Elite kit,Victor Laboratories,Burlingame,CA)。通过与3,3’-二氨基联苯胺四氯化氢(DAB,Sigma Chemical Co.,St Louis,MO)反应完成检测。(参见,Cao Z等.The angiotensin type 2 receptor is expressed in adult ratkidney and promotes cellular proliferation and apoptosis.Kidney Int.2000;58:2437-2451)。
最后,可以理解,在不背离本发明的精神下,可得到多种其他的修正和/或改变。
Claims (32)
1.一种改变细胞产生的细胞外基质(ECM)蛋白水平的方法,所述方法包括调节细胞分裂自身抗原(CDA)的表达或活性。
2.根据权利要求1所述的方法,其中所述ECM蛋白选自胶原、弹性蛋白、原纤蛋白、纤连蛋白、层粘连蛋白和蛋白聚糖。
3.根据权利要求1所述的方法,其中所述ECM蛋白是纤连蛋白或胶原IV。
4.根据权利要求1所述的方法,其中所述细胞来源于肾脏组织或者血管组织。
5.根据权利要求1所述的方法,其中所述细胞选自肾足细胞,肾近端小管细胞,肾集合管细胞,泡沫细胞和巨噬细胞。
6.根据权利要求1所述的方法,其中所述CDA包括N-端脯氨酸富集区,中心碱性区和C-端双酸区。
7.根据权利要求1所述的方法,其中所述CDA是细胞分裂自身抗原1(CDA1),或其片段,功能等同物,类似物,突变体或变体。
8.根据权利要求7所述的方法,其中所述CDA1由如附图7所示核苷酸序列编码。
9.根据权利要求7所述的方法,其中所述CDA1包含附图8所示氨基酸序列或其功能等同物或衍生物。
10.一种治疗或预防ECM蛋白合成相关状况的方法,该方法包括调节CDA的表达和/或活性。
11.根据权利要求10所述的方法,其中所述状况是纤维化。
12.根据权利要求11所述的方法,其中所述纤维化是由于烧伤、心脏病发作、化疗药物治疗、暴露于放射线或手术。
13.根据权利要求11所述的方法,其中所述纤维化是主要器官纤维化。
14.根据权利要求13所述的方法,其中所述主要器官选自肾脏、肝脏、心脏和眼睛。
15.根据权利要求13所述的方法,其中所述主要器官纤维化是由于选自由以下成员构成的组的状况:糖尿病、高血压、病毒性肝炎、酒精滥用、黄斑变性、视网膜病变和玻璃体视网膜病变。
16.根据权利要求11所述的方法,其中所述状况是糖尿病引起的肾脏纤维化。
17.根据权利要求10所述的方法,其中所述状况选自全身和局部硬皮病、瘢痕瘤、肥大瘢痕、动脉粥样硬化和再狭窄。
18.根据权利要求17所述的方法,其中所述状况是动脉粥样硬化。
19.根据权利要求10所述的方法,其中所述状况是动脉瘤。
20.根据权利要求19所述的方法,其中所述动脉瘤是腹部动脉动脉瘤。
21.根据权利要求10所述的方法,其中所述CDA是CDA1。
22.一种用于研究ECM紊乱的非-人动物,所述动物包含能以改变的水平表达CDA的细胞。
23.根据权利要求22所述的非-人动物,其中所述CDA是CDA1。
24.一种筛选能够调节ECM合成的试剂的方法,所述方法包括下列步骤
提供能表达CDA的动物或者细胞,
将所述动物或者细胞暴露于所述试剂,和
测定试剂对CDA表达和/或活性的影响。
25.根据权利要求24所述的方法,其中所述CDA是CDA1。
26.一种根据权利要求24所述方法鉴定的试剂。
27.一种药物组合物,所述组合物包括权利要求26所述试剂。
28.一种治疗或预防ECM蛋白相关状况的方法,所述方法包括对需要所述治疗或预防的动物施予有效量的权利要求27所述的药物组合物。
29.一种调节细胞中CDA表达和/或活性的方法,所述方法包括将细胞暴露于能调节因子表达和/或活性的试剂,所述因子选自血管紧张素II、TGFβ和结缔组织生长因子。
30.根据权利要求29所述方法,其中所述CDA是CDA1。
31.一种诊断动物中ECM蛋白合成相关状况的方法,所述方法包括
从所述动物中获得生物样本,
测定所述样本中的CDA水平,和
比较所述样本中的CDA水平和参考值
其中,如果所述样本中的CDA水平统计学意义上显著高于或低于参考值,则诊断为阳性。
32.根据权利要求31所述方法,其中所述CDA是CDA1。
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CN110178792A (zh) * | 2019-05-07 | 2019-08-30 | 哈尔滨医科大学 | 一种动脉粥样硬化易损斑块小鼠模型的构建方法 |
CN115443947A (zh) * | 2022-10-12 | 2022-12-09 | 江苏省人民医院(南京医科大学第一附属医院) | 高血压动物模型的制备方法 |
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US7214375B1 (en) * | 1989-09-29 | 2007-05-08 | La Jolla Cancer Research Foundation | Methods of decreasing the accumulation of extracellular matrix associated with glomerulonephritis with anti-TGF-β-specific antibodies |
US5408040A (en) * | 1991-08-30 | 1995-04-18 | University Of South Florida | Connective tissue growth factor(CTGF) |
US6211217B1 (en) * | 1999-03-16 | 2001-04-03 | Novartis Ag | Method for reducing pericardial fibrosis and adhesion formation |
AUPR121300A0 (en) * | 2000-11-03 | 2000-11-30 | Monash University | Cell division autoantigen (CDA) polypeptides, gene sequences and uses thereof |
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CN110178792A (zh) * | 2019-05-07 | 2019-08-30 | 哈尔滨医科大学 | 一种动脉粥样硬化易损斑块小鼠模型的构建方法 |
CN115443947A (zh) * | 2022-10-12 | 2022-12-09 | 江苏省人民医院(南京医科大学第一附属医院) | 高血压动物模型的制备方法 |
CN115443947B (zh) * | 2022-10-12 | 2023-11-21 | 江苏省人民医院(南京医科大学第一附属医院) | 高血压动物模型的制备方法 |
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JP2008500264A (ja) | 2008-01-10 |
WO2005002614A1 (en) | 2005-01-13 |
US20070185020A1 (en) | 2007-08-09 |
CA2530866A1 (en) | 2005-01-13 |
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