CN1677078A - 制备高密度阵列的方法 - Google Patents

制备高密度阵列的方法 Download PDF

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Publication number
CN1677078A
CN1677078A CNA2005100688309A CN200510068830A CN1677078A CN 1677078 A CN1677078 A CN 1677078A CN A2005100688309 A CNA2005100688309 A CN A2005100688309A CN 200510068830 A CN200510068830 A CN 200510068830A CN 1677078 A CN1677078 A CN 1677078A
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target substance
high density
line
density arrays
wire harness
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CN100367023C (zh
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J·R·小哈德森
E·P·道森
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BioVentures Inc
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BioVentures Inc
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Abstract

一种制备目标物质的高密度阵列的方法，包括切割一束目标线的步骤，其中目标线包含目标物质，其中切割得到多个高密度阵列，此外，本发明方法可包括额外的步骤，如稳定化目标线或线束，向高密度阵列中掺入一种或多种其它材料，及检查高密度阵列。同样，制备了根据本方法的高密度阵列。

Description

制备高密度阵列的方法
背景
固定化的天然或合成的目标物质的高密度阵列允许在同一时间筛选分析物中是否存在特定的性质。已在许多技术领域证明了这种高密度阵列的用途，包括化学、遗传学、免疫学、材料科学、医药、分子生物学和药理学。例如，核酸高密度阵列可用于证实基因序列，检测遗传突变的存在与否，以及定性和定量检测基因产物的差异表达。类似地，肽高密度阵列可用于绘制引发免疫应答的表位序列图谱。此外，目标物质阵列可用于鉴定用来开发药物的化合物。
目前，用于构建待测物的高密度阵列的方法一般有两种。第一种，是将预制的天然或合成目标物质(如生物分子)单独地直接施加于支持物上的特定位置。支持物包括硝酸纤维素膜、尼龙膜、聚二氟乙烯膜、玻璃、硅或其它材料，可通过将支持物暴露于紫外线照射或通过焙烤支持物或其它技术将目标物质固定于支持物上。一种这样的方法公开于Pietu等人，“通过高密度cDNA阵列的定量杂交揭示的人肌肉中优势表达的新基因转录子”，基因组研究(Genome Research)，(1996)6：492-503，此处全文引入作为参考。已设计了多种设备以使应用方法自动化。
第二种构建高密度阵列的方法涉及，于支持物的特定位点上原位合成单独的目标物质。在一种这样的方法中，使用光合成化学以在支持物上独特位点处同时制备一系列不同的目标物质。在另一种这样的方法中，通过物理性地掩蔽或封闭支持物上的所选区域，且在未掩蔽的支持物上的部分进行所需化学合成反应，合成了目标物质。这种方法的实例公开于Fodor等人，“光指导的空间上可确定的平行化学合成”，科学，(1991)，251：767-777；美国专利5,436,327；Southern E.M.等人，“通过与寡核苷酸阵列杂交分析并比较核酸阵列；利用实验模型评价”，基因组学(Genomics)，1992，13：1008-1017，此处全文引入作为参考。
上述两种高密度阵列构建方法均有许多缺点。首先，一次仅能制备相对有限数量的相同阵列。第二，很难在生产中检查由这些方法制备的阵列以确定生产步骤的完整性。第三，用目前的方法无法将许多潜在的目标物质施加于支持物上，也不能于支持物上原位合成。另外，未描述由多于一种化学种类的待测物组成的阵列，如肽和核酸待测物组成的阵列。还有，这些方法仅能在具有相对有限厚度的片层上制备目标物质阵列。再者，每种方法只能制备区域面积尺寸相对有限的目标物质阵列。
因此需要制备高密度阵列的替代方法，其不具有已知高密度阵列制备方法中固有的缺陷。例如，该方法应能优选地可同时、快速且经济地制备大量相同的阵列。该方法应能使用多种多样的目标物质和支持物，包括不能被目前方法掺入阵列的待测物和支持物。该方法应能以多种厚度和尺寸制备多于二维的阵列，且可为除了平面形状之外的形状。另外，该方法应可制备具有多种目标物质区域面积的阵列，包括在一块阵列上不同目标物质的不相类似的尺寸的区域。而且，该方法应能制备来自不同类型或化学种类的待测物的高密度阵列，如肽和核酸待测物的阵列。此外，该方法应能使用预制的目标物质(或需要时于原位合成的目标物质)以结合这些方法的优点。
发明概述
根据本发明的一个方面，提供了一种制备目标物质的高密度阵列的方法，包括切割一束目标线的步骤，其中目标线包含目标物质，其中切割得到高密度阵列。该方法也包括稳定化线束，向线束中掺入其它物质，及检查高密度阵列的步骤。
本发明还提供了一种通过切割含有多个目标线的线束制备的高密度阵列，其中多个目标线包含目标物质。高密度阵列可具有存在于一个、两个或三个笛卡尔坐标上的目标物质。
本发明还提供了一种制备高密度阵列的方法，包括将包含目标物质线的膜卷曲或堆叠以制备线束的步骤。还提供了利用根据本发明制备的高密度阵列确证基因序列、检测遗传突变的存在与否、定性或定量检测基因产物的差异表达、绘制引发免疫应答的表位序列图谱、或用于鉴定用来开发药物的化合物的方法。
附图说明
参考下列描述、所附权利要求书及附图可更好地理解本发明的特点、方面和优点，其中：
图1-图3，描绘用包含本发明的目标物质的纤维束制备高密度阵列；
图4-图5，描绘用含膜的线束制备高密度阵列，其中膜具有根据本发明施加于膜上的目标物质的线；
图6-图8，描绘用包含多个膜的线束制备高密度阵列，其中膜具有根据本发明施加于膜上的已知目标物质的线；
图9-图11，描绘用包含卷曲膜的线束制备高密度阵列，其中膜具有根据本发明施加于膜上的已知目标物质的线；
图12-图14，描绘用包含管的线束制备高密度阵列，其中根据本发明管用目标物质填充；
图15是放射自显影图，显示于依本发明制备的阵列上进行的杂交研究结果；以及
图16是放射自显影图，显示于依本发明制备的另一个阵列上进行的杂交研究结果。
发明描述
根据本发明的一个实施方案，提供了一种制备目标物质的高密度阵列的方法，其用于测定分析物的身分或性质，或用于测定目标物质的身分或性质。根据本发明的另一个实施方案，提供了用于测定分析物的身分或性质，或用于测定目标物质的身分或性质的目标物质的高密度阵列。
如此处所用，术语“目标物质”是指有能力与一种或多种目标分析物相互作用的高密度阵列的成分。目标物质可为原子、分子、复合化学物、细胞器、病毒、细胞或其它材料，或这些物质的组合，或参考此处所述可为本领域技术人员理解的其它物质。例如，依本发明的高密度阵列的目标物质可选自一种或多种原子，如锌、硫和金；生物分子如多核苷酸、DNA、RNA、肽、蛋白质、糖蛋白、脂蛋白、碳水化合物、脂类、免疫球蛋白及其合成类似物与变异体；病毒；亚细胞成分如显微解剖的染色体和线粒体；细胞，包括原核细胞、古细菌和真核细胞；以及其它材料，如金属合金、陶瓷、玻璃、半导体、超导体、塑料、聚合材料、木材、织物和凝结物。
如此处所用，术语“分析物”是指通过在根据本发明的高密度阵列上与目标物质相互作用待测定身分或性质的那些物质。或者类似地，可使用分析物通过与在根据本发明的高密度阵列上与目标物质相互作用测定目标物质的身分或性质。还可从如目标物质的相同组中选择分析物，如蛋白质或核酸，或其可是一种物理或环境条件，如选自温度、pH或盐浓度的一种或多种条件。
如此处所用，术语“目标线”是指目标物质的线。这些线全部由一种或多种目标物质构成，或可含有一种或多种带有支持物或容器的目标物质。目标物质可吸附于、结合于、包埋入或包被在支持物上，或含于容器中。例如，目标线包括目标物质(如金属合金、凝结物或塑料)的浇铸棒(cast rod)，或可包括吸附于玻璃纤维或丝线上的目标物质，结合于聚合纤维的、包埋入多孔棒、包被于金属丝或含于明胶基质中的目标物质。另外，目标线可包含书写、刻划、印制或模压在玻璃载玻片(或诸如聚合物薄平面板的膜、或等效支持物)上的目标物质的线。另外，目标线可包括结合于管内侧的目标物质。
如此处所用，术语“基质”指目标物质可包埋入的或可结合于其上的材料以提供额外的结构性支持，作为间隔基，将目标物质展示给分析物，或影响目标物质与分析物之间的相互作用，如：通过将目标物质相互之间电绝缘。基质可为聚合材料，如一种或多种选自气溶胶、琼脂糖、白蛋白、明胶、水凝胶和聚丙烯酰胺的物质。
如此处所用，术语“束”指一种有序排列或装配的目标线。例如，一束可包括一堆目标线，其中每个目标线包含用目标物质填充的管，或其中每个目标线包含刻划于膜上的目标物质的线，或其中每个目标线包含目标物质的线。
制备高密度阵列的方法
依本发明制备高密度阵列的方法，包括步骤a)装配目标线束，和步骤b)切割线束产生阵列。另外，该方法可包括稳定化目标线或线束的步骤。再有，该方法可包括将一种或多种其它材料掺入高密度阵列的步骤。还有，该方法可包括检查高密度阵列的步骤。
装配目标线束
可通过多种方法制备阵列束。例如，首先，通过用目标物质或与一种基质结合的目标物质填充管制备目标线束。目标物质可不经与基质化学结合而包封于基质中，或可通过共价结合、离子相互作用、氢键或其它形式的结合而结合到基质上。然后，排列管，将其基本上沿长轴固定形成目标线束。
还可首先通过用目标物质包被或包埋一种支持物(诸如膜、纤维、管或棒)；或用自来水钢笔尖(如用艺术家的鸦羽管)或喷枪(air brush)将目标物质溶液加至支持物上；或通过喷墨打印机的方法将目标物质溶液模压于或热转移于支持物上。然后，将这些支持物堆积、卷曲或折叠以制备目标线束。所得线束含有目标物质的行列，其相对于所用目标物质的长轴平行排列。
切割线束以制备阵列
装配后，切割线束以制备阵列。可用显微切片机、激光、锯、热线(hot wire)或其它工具，或参照此处公开可为本领域技术人员理解的其它方法切割线束。切割可产生具有多种任意厚度的目标物质的高密度阵列。例如，阵列可具有厚度为约0.1μm至约1mm或更厚的目标物质。此外，与现有已知的制备阵列的方法不同，此处公开的方法可方便的制备具有目标物质厚度大于50μm的阵列。这是一种优点，因与在较薄阵列上的目标物质产生的信号相比，这样可增加由目标物质产生的信号。
在一个优选实施方案中，装配的线束具有长轴基本上相互平行的目标线，且线束被以基本上垂直于目标线长轴的方式切割，以产生高密度阵列。切割也可以除了基本上垂直于目标线长轴以外的角度进行，例如，从cyclindrical束制备椭圆形阵列。
根据线束形状及切割方向，切割步骤可产生具有一种、两种或三种解析坐标(analytic axe)的高密度阵列，即高密度阵列带有位于一个、两个或三个位于笛卡尔坐标的目标物质。例如，通过横切具有位于单一平面上的目标物质的线束可得有一个解析坐标轴的阵列。通过横切具有位于多个平面上的目标物质的线束可得有两个解析坐标轴的阵列。通过结合多个单一解析坐标轴的阵列可制备具有两个解析坐标轴的阵列。通过结合多个单一解析坐标轴的阵列，或通过结合单一解析坐标轴阵列与两个解析坐标轴的阵列，或通过结合多个具有两个解析坐标轴的阵列，可制备具有三个解析坐标轴的阵列。
例如，具有一个解析坐标轴的高密度阵列可通过如此切割这样的线束制备，其中线束由通过在平面膜上以平行线沉积目标物质制成的目标线形成，而切割是在垂直于由线所形成的平面的平面上进行。类似地，具有两个解析坐标轴的高密度阵列可通过如此切割这样的线束制备，其中线束由包含堆叠膜的目标线形成，其中每个膜上有以平行线沉积的目标物质，而切割是在垂直于目标物质线长轴的平面上进行。此外，可通过堆叠由上述切割制备的具有两个解析坐标轴的多个高密度阵列，制备具有三个解析坐标轴的高密度阵列。
稳定化目标线束
根据本发明制备高密度阵列的方法可还包括稳定化目标线束的步骤。稳定可改善线束或阵列的形式或功能，如使线束更易于切割，或易于从阵列中将目标物质彼此分隔开。可于目标线束装配过程中或装配后的任何时间进行稳定化步骤，只要适于稳定的类型即可。例如，稳定可通过将目标线束包埋于如环氧、聚丙烯或聚苯乙烯基质中完成。向高密度阵列掺入其它材料
依本发明制备高密度阵列的方法还可包括在目标线束装配过程中或之后(包括切割步骤后)向高密度阵列掺入一种或多种其它材料的步骤。这些材料可改善高密度阵列的形式或功能。例如，掺入步骤可包括添加抗氧化剂或微生物抑制剂或其它物质，以使高密度阵列在一定时间内维持稳定。
另外，掺入步骤可包括向基质中加入降低背景噪音的物质，如非荧光计数染料(counterstain)，或增加检测信号的物质。类似地，掺入步骤可包括向基质中添加闪烁剂以促进放射活性分析物的检测。还有，掺入步骤可包括向基质中加入用于特定检测模式所需的辅因子，如用于酶促颜色形成所需的次级酶，或可增强荧光标记检测的能量转移染料。另外，由此处公开的方法制备的高密度阵列的表面可用银或其它反射性材料包被，以增强可用于检测的光量。
检查高密度阵列
根据本发明制备高密度阵列的方法还可包括检查高密度阵列的步骤。在一个优选实施方案中，检查步骤选自用或不用放大的可见光检查、化学沉积、电探查、机械感应和磁感应。在另一实施方案中，检测步骤包括将阵列置于紧邻一系列叉指型(interdigitated)电极处，测量由于高密度阵列上的目标物质与叉指型电极相互作用造成的电容改变。
从包含纤维的线束中制备高密度阵列
在一个实施方案中，从包含纤维(fiber)或线(thread)的目标线束中制备高密度阵列。所述纤维或线可含有天然或合成材料(选自棉、丝、尼龙或聚酯)，或是参照此处公开可为本领域技术人员理解的其它材料。
在一个优选实施方案中，目标线束是通过直接将纤维浸渗目标物质的水溶液中制备的。将一系列这种纤维用不同的目标物质浸渗，于数据库中记录每种纤维所含目标物质的身分。洗涤纤维以洗脱未结合的目标物质，并用非干扰性物质封闭纤维及固定化的目标物质上的非特异性结合位点。干燥纤维以将封闭剂固定于纤维及固定化的目标物质上。
将纤维装配成线束，并将每一纤维及其结合的固定化目标物质记录于数据库。优选地通过包埋或将线束浸入基质来稳定纤维束，从而提供了对线束的结构性支持。
然后利用适当的装置以基本上垂直于纤维长轴的方式切割线束，提供多个高密度阵列。优选地，切割得到了多个相同的高密度阵列。每一阵列上的目标物质的身分和位置均通过数据库中的信息显示踪迹。这些阵列可用于在同一时间筛选分析物中特定性质的存在与否，或结合此处的公开如本领域技术人员所理解可用于其它目的。
参照图1-3，其中分别显示了目标线10包含一系列用已知目标物质浸渗的经包被的纤维12；包埋于基质14的目标线10并被装配成线束16；以及经切割的线束16以制备多个相同的高密度阵列18，其中每一阵列具有位于两个解析坐标轴上的目标物质。
从包含膜的线束中制备高密度阵列
在一个实施方案中，从包含膜的线束中制备高密度阵列。膜可包含聚合物质的薄平面片层，或可包含参照此处公开可为本领域技术人员理解的其它材料。
在一个优选实施方案中，线束是通过将含有目标物质的组成成分之线通过书写、刻划、印制或模压施加于膜上而制备的。于数据库中记录每种目标物质的身分和位置。如需要可处理膜，以将目标物质固定于膜上。
可切割以此种方法制备的膜，以制备多个高密度阵列，每一阵列具有以一个解析坐标轴排列的目标物质。参照图4和5，其中分别显示了线束20包含具有其上施加了已知目标物质24的线的膜22；以及经切割的线束20以制备多个高密度阵列26，其中每一阵列具有位于一个个解析坐标轴上的目标物质。
或者，可将如此制备的多个膜以如数据库中记录的每一固定化的目标物质之身分和位置装配入线束。装配可包括卷曲或折叠膜，或可包括堆叠多个浸渗了目标物质的膜。如需要，通过将线束包埋或浸渗入基质中稳定线束，以提供对线束的结构性支持。
然后利用适当的装置以基本上垂直于膜上目标物质线的长轴的方式切割线束，提供多个高密度阵列，其中每一阵列具有排列于两个解析坐标轴上的目标物质。优选地，切割得到了多个相同的高密度阵列。目标物质的身分和位置均通过数据库中的信息显示踪迹。这些阵列可用于在同一时间筛选分析物中特定性质的存在与否，或结合此处的公开如本领域技术人员所理解可用于其它目的。
参照图6-8，其中分别显示了多个膜28具有施加于各个膜28上的目标物质线30；堆叠并稳定膜28以形成线束32；以及切割线束32以制备多个高密度阵列34，其中每一阵列具有排列于两个解析坐标轴上的目标物质28。
参照图9-11，其中分别显示了膜36具有施加于膜36上的已知目标物质线38；卷曲并稳定膜36以形成线束40；以及切割线束40以制备多个高密度阵列42，其中每一阵列具有排列于两个解析坐标轴上的目标物质38。
从包含管的线束中制备高密度阵列
在一个实施方案中，从包含管的目标线中制备高密度阵列。管可包括聚酰亚胺、尼龙、聚丙烯、聚氨基甲酸乙酯、硅酮、乙基乙烯基乙酸酯、不锈钢、铜、玻璃或熔凝硅石，或是参照此处公开可为本领域技术人员理解的其它材料。
在一个优选实施方案中，通过用目标物质的水溶液包被管内侧制备目标线，使得目标物质被吸附、结合或共价结合于管的内表面。或者，可用含有或不合包埋于基质中的目标物质之目标物质填充管。通过用不同目标物质包被或填充管制备一系列这种管，并将每一目标线及其含有的目标物质的身分记录于数据库。
依记录在数据库中的每一管的位置及其结合的目标物质将各个管装配成线束。优选地通过将线束包埋于基质中来稳定管的线束，从而对线束提供结构性支持。
然后利用适当的装置以基本上垂直于管的长轴的方式切割线束，提供多个高密度阵列。优选地，切割得到了多个相同的高密度阵列。目标物质的身分和位置均通过数据库中的信息显示踪迹。这些阵列可用于在同一时间筛选分析物中特定性质的存在与否，或结合此处的公开如本领域技术人员所理解可用于其它目的。
参照图12-14，其中分别显示了目标线44包含一系列用已知目标物质48填充的管46；包埋于基质50中的目标线44被装配成线束52；以及经切割的线束52用于制备高密度阵列54，其中每一阵列具有位于两个解析坐标轴上的目标物质48。
实施例1  含有DNA包被的线之高密度阵列的制备及用途
根据本发明从含有纤维或线的线束中制备高密度阵列的方法用于制备如下DNA目标物质的高密度阵列。通过将线浸入水中评估了棉线的可湿润性。在线表面上成珠的水表明其表面上带有可对用于制备线束的线的可湿润性产生负面影响的结合物、油或其它材料。如果在可湿润性检测中存在成珠现象，则应将线于甲醇、乙醇或其它适当的可与水混溶的溶剂中进行洗涤，以除去不希望的材料。然后将线置于水中，经过数次水交换，直至每一线均充分湿润。
然后，将线转移入诸如聚L-赖氨酸的聚合阳离子物质的水溶液中，与聚L-赖氨酸溶液平衡数小时。从聚L-赖氨酸溶液中移出线并干燥，将聚L-赖氨酸固定于线的表面。固定后，于缓冲液中洗涤线，更换缓冲液数次。从缓冲液中移出线并干燥。
然后，根据待构建的线束尺寸将线束切割成从数厘米至数米的不同长度。优选的将用于线束的每一线切割成相同长度。
然后，将每一切割的线置于具有特定已知序列DNA(待固定化的目标物质)的溶液中。优选地，对每一线而言DNA序列不同。如果用于核酸杂交研究，所用的DNA优选地为单链，但也可为双链形式。DNA可来自天然来源如质粒制剂、酵母人工染色体、BAC文库、YAC文库或其它DNA文库(如表达序列标签，EST)，也可通过聚合酶链反应或其它合成方法合成制备。将线与DNA溶液温育数分钟至数小时的时间，这可根据DNA充分浸润线上可得的结合位点的需要。
于约60℃的灶中干燥DNA包被的线一段足以将DNA固定至线上的时间。或者，可通过将干燥的DNA包被的线用100％乙醇或甲醇湿润数分钟然后使线干燥，将DNA固定于线上。将每一线的身分和其固定化DNA目标物质的序列记录于数据库。然后，单独于诸如1x TE缓冲液(10mMTris，1mM EDTA，pH7.6)中洗涤线以从线上除去未结合的DNA。再次干燥DNA包被的线。
然后，根据记录在数据库中之线束中每一线的位置及其结合的DNA，通过将线平行并彼此相邻地排列，装配DNA包被的线的线束。通过将其包埋于下列基质中稳定线束，这些基质如聚甲基丙烯酸酯、环氧树脂、聚乙二醇、石蜡、橡胶、聚丙烯酰胺和其它材料，可优选地于高温下以液体形式处理，或以适于包埋线的非聚合形式处理。使包埋的线硬化，或使其交联以赋予线束刚性结构。
在一个优选实施方案中，通过用基质不能渗透的诸如明胶、蔗糖或聚乙烯醇的物质包被线，以防止线被包埋基质完全浸渗或隔绝固定化的DNA。通过将带有固定化的DNA之线于含有约0.01％-约10％重量百分比的所述物质之溶液中湿润，并在被包埋入基质前使线干燥来实现这一点。
然后用显微切片机或类似仪器以垂直于线长轴的方式切割稳定化的线束，产生优选地具有厚度约为0.1至100μm的多个高密度阵列。每一所得高密度阵列具有位于阵列上特定空间区域或区带的相同DNA模式，目标物质排列在两个解析坐标轴上。
这种DNA阵列的一种用途，是在与阵列中单链DNA目标物质互补之样品中检测标记的DNA序列，方法是通过在杂交条件下将样品与阵列温育足以使杂交发生的一段时间。洗涤除去未杂交的DNA。然后检测标记，测定产生信号的区带。将这些区带与含有阵列上DNA目标物质身分的数据库比较，确立样品中标记DNA的身分。
实施例2  含有肽包被的线之高密度阵列的制备及用途
根据本发明从含有纤维或线的线束中制备高密度阵列的方法用于制备如下肽目标物质的高密度阵列。通过将线浸入水中评估了棉线的可湿润性。在线表面上成珠的水表明其表面上带有可对用于制备线束的线的可湿润性产生负面影响的结合物、油或其它材料。如果在可湿润性检测中存在成珠现象，则应将线于甲醇、乙醇或其它适当的可与水混溶的溶剂中进行洗涤，以除去不希望的材料。然后将线置于水中，经过数次水交换，直至每一线均充分湿润。
然后，将线转移入诸如聚L-赖氨酸的聚合阳离子物质的水溶液中，与聚L-赖氨酸溶液平衡数小时。从聚L-赖氨酸溶液中移出线并干燥，将聚L-赖氨酸固定于线的表面。固定后，于缓冲液中洗涤线，更换缓冲液数次。从缓冲液中移出线并干燥。
然后，根据待构建的线束尺寸将线束切割成从数厘米至数米的不同长度。优选的将用于线束的每一线切割成相同长度。通过水溶液的可湿润性评价棉线。将线转移入含有诸如聚L-赖氨酸的聚合阳离子物质的水溶液中，与聚L-赖氨酸溶液平衡数小时。从聚L-赖氨酸溶液中移出线并干燥，将聚L-赖氨酸固定于线的表面。固定后，于缓冲液中洗涤线，更换缓冲液数次。从缓冲液中移出线并干燥。
然后，将每一切割的线置于具有特定已知序列的肽(待固定化的目标物质)的二甲亚砜(DMSO)溶液中。优选地，对每一线而言肽不同。用做目标物质的单独的肽可为市售，或可用Merifield合成制备(如Bodanszky，M和Troust，B.编辑，肽合成原理，第2版，Springer-Verlag，纽约，1993，此处引入作为参考)，参照此处的公开可为本领域普通技术人员所理解。将每一线与肽溶液温育数分钟至数小时的时间，这可根据肽充分浸润线上可得的结合位点的需要。
吸干肽包被的线，使之不含过量DMSO溶液，然后与混合的戊烷或等同物一起温育，将肽沉淀于线表面。于室温或约60℃-70℃下(真空或非真空)干燥肽包被的线。将每一线的身分和其固定化肽目标物质的序列记录于数据库。然后，于诸如0.1-1M Tris(pH7.0)或磷酸缓冲盐液(pH7.0)、诸如120mM氯化钠、2.7mM氯化钾和10mM磷酸盐(获自Sigma化学有限公司，St.Louis，MO，美国)洗涤肽包被的线，以从线上除去未结合的肽。室温下或约60℃-70℃下(真空或非真空)再次干燥线。
然后，根据记录在数据库中之线束中每一线的位置及其结合的肽，通过将线平行并彼此相邻地排列装配肽包被的线的线束。通过将其包埋于下列基质中稳定线束，这些基质如聚甲基丙烯酸酯、环氧树脂、聚乙二醇、石蜡、橡胶、聚丙烯酰胺和其它材料，可优选地于高温下以液体形式处理，或以适于包埋线的非聚合形式处理。使包埋的线硬化，或使其交联以赋予线束刚性结构。
在一个优选实施方案中，通过用基质不能渗透的诸如明胶、蔗糖或聚乙烯醇的物质包被线，以防止线被包埋基质完全浸渗或隔绝固定化的肽。通过将带有固定化的肽之线于含有约0.01％-约10％重量百分比的所述物质之溶液中湿润，并在被包埋入基质前使线干燥来实现这一点。
然后用显微切片机或类似仪器以垂直于线长轴的方式切割稳定化的线束，产生优选地具有厚度约为0.1至100μm的多个高密度阵列。每一所得高密度阵列具有位于阵列上特定空间区域或区带的相同肽模式。
这种肽阵列的一种用途，是从样品中检测抗体分析物，样品中的抗体至少可结合于阵列上的一种肽目标物质。检测抗体分析物存在与否的方法是通过在适当条件下于足以使抗体分析物与肽发生结合的一段时间中将样品与阵列温育。洗涤除去未结合的样品。根据本领域技术人员知晓的技术用生物素化第二抗体及标记的链亲和素(如碱性磷酸酶标记、荧光素标记或金标记的链亲和素)检测结合的抗体。参考数据库，确立显示结合的区带上肽目标物质的身分。结合表明存在具有针对区带上的肽的表位结构域之抗体。如样品来自患者血清，这种结合可为接触或感染某种生物的证据。
实施例3  带有浸渗于膜上的DNA的高密度阵列的制备及用途
根据本发明制备目标物质的高密度阵列的方法用于从如下浸渗于膜上的DNA制备阵列。使用斯坦福大学(Palo Alto，California，美国)的酵母属基因组数据库作为用于鉴定天然存在的基因组序列的信息来源。使用这些信息，从酵母基因组中随机选取了16个具有相似熔解温度的寡核苷酸作为目标物质。每一序列在28-35个核苷酸之间，根据公开于Gait，M.J.编辑，寡核苷酸合成实用指南，IRL出版社，Oxford，1984中的方法用标准氰乙基氨基亚磷酸酯化学方法合成。每一目标物质序列在3’端具有100个胸苷以促进寡核苷酸向膜的结合。见如，Erlich，Henry，A.和Bugawan，Teodorica，L.，II类HLA基因多态性：基因分型、进化、和于疾病易感性的关系，PCR技术：DNA扩增的原理及应用，Stoclton出版社，纽约，193-208，1989，此处全文引入作为参考。标记为#1至#16的16个目标物质分别溶解于焦碳酸二乙酯处理过的水中至终浓度为10微克/微升。
使用具有容积为11微升储液槽的加样尖施加目标物质，其中储液槽与加样尖通过小容积导管连接。使用加样尖于20cm×20cm的HybondTMN+带电膜(Amersham，Arlington Heights，IL，美国)上以约1mm至3mm的间距划目标物质线。用一种Eppendorf2-10微升加样器以10.5微升前16个目标物质的溶液填注加样尖储液槽。
将第一张膜(#1膜)置于洁净平整的台面，其中在膜与台面之间放置的制造商包裹中以一张大于膜的蜡纸用做分隔物。排列加样尖使得毛细导管的两侧均接触到距膜边缘1cm的蜡纸，使用尺作为引导，手工在蜡纸和膜上平滑划动加样尖，划出与膜的一个边缘平行的目标物质的直线。目标物质溶液从加样尖移出，在划出约12-16cm长的线后耗尽。在第一张膜上对每一目标物质溶液重复这一循环，直至#1膜含有相互间隔约1mm至3mm的不同DNA目标物质的16条平行线。
重复这一步骤再制备两张膜#2膜和#3膜，除了顺序三次施加每一种DNA目标物质，在#2膜和#3膜上得到总共48条目标物质平行线。在所有膜上标记目标物质的每一条线用于鉴别。
含有目标物质DNA线的膜空气干燥约2小时，然后通过使用Stratagene 2400 Stratalinker(Stratagene，La Jolla，CA，美国)应用1200微焦耳的UV电磁辐照35秒进行交联。从含有目标物质线前导边缘的膜的边缘开始，从三张膜的每一张中切下宽约2cm长约20cm的条带，使目标物质线与条带的2cm边缘平行。
使用标准技术制备互补于目标物质#1和#7的序列的放射性标记的DNA探针。使用标准技术试图在放射性标记的探针与从#1膜制备的阵列之间进行杂交。总之，根据制造商指示，用γ-32uP-ATP(ICN放射化学公司，Irvine，CA，美国)使用Ready-to-go KinaseTM试剂盒标记DNA寡核苷酸。根据制造商指示，用NickTM柱(Pharmacia)纯化标记的探针，稀释至约1×106cpm/ml。
根据制造商指示，用10毫升HyperHybTM缓冲液(Research Genetics，Inc.Huntsville，AL，美国)在Mini-6TM(Hybraid，Ltd.，Middlesex，英国)杂交炉中42℃各自预杂交和杂交一小时。用10毫升1x SSC，0.01％十二烷基硫酸钠(SDS)42℃下洗涤15分钟，共进行3次，完成杂交后的洗涤。最终的洗涤在100毫升1x SSC(0.15M氯化钠，0.015M柠檬酸钠，pH7.2)，0.01％SDS(Sigma)中42℃下洗涤15分钟。在10毫升1x SSC缓冲液中进行最后漂洗。室温下空气干燥膜1-2小时。
室温下，将阵列与BiomaxTMMMS或MR x-射线胶片(Eastman Kodak，Rochester，NY，美国)接触进行放射自显影约0.5-4小时，直至获得期望的影像强度。所有与阵列上适当的目标物质杂交的探针证明，DNA目标物质已结合到膜上，可用于探查，且这种探查可得到特异性的确定的杂交结果。
然后，如下使用#1膜、#2膜和#3膜之剩余的20cm×18cm部分制备阵列。将膜浸入3％硬骨鱼类明胶(Sigma)的去离子水溶液中，室温下温育过夜以封闭膜。再将膜于600毫升去离子水中洗涤三次，除去未结合的明胶。将膜于两层903吸水纸之间(Schleicher and Schuell，Keene，NH，美国)吸去过量水分，室温下空气干燥过夜。
从#1膜、#2膜和#3膜三张膜每一张上以垂直于目标物质线的方式切割2cm×20cm的条带，使2cm边缘与目标物质线平行。将每一条带沿平行于目标物质线的轴紧紧卷曲，制备使未施加目标物质的膜部分为圆柱体最内部的一种圆柱体。使用透明指甲油封闭3mm宽的自由条带边缘以防止圆柱体松开。每一圆柱体浸入1.25cm×7.5cm的塑料球中，其中灌注了根据制造商指示制备的非聚合LR WhiteTM软包埋基质(Sigma)，直到圆柱体被基质充分浸渗。然后将每一圆柱体置于灌注有基质的球的底部，居中并使之于60℃聚合过夜。移出每一含有经包埋的圆柱体的球，置于环境温度，观察到聚合完全。
然后通过以垂直于其长轴的方式，即垂直于每一目标物质线的长轴反复切割每一包被的圆柱体，制备厚度约10μm的多个阵列。使用DK-10型手动显微切片机(Edmund Scientific，Barrington，NJ，美国)完成切割。
使用标准技术制备互补于目标物质#1和#7的序列的放射性标记的DNA探针。使用标准技术试图在放射性标记的探针与从#1膜制备的阵列之间进行杂交。总之，根据制造商指示，用γ-32P-ATP(ICN放射化学公司，Irvine，CA，美国)使用Ready-to-go KinaseTM试剂盒标记DNA寡核苷酸。根据制造商指示，用NickTM柱(Pharmacia)纯化标记的探针，稀释至约1×106cpm/ml。
根据制造商指示，用10毫升HyperHybTM缓冲液(Research Genetics，Inc.Huntsville，AL，美国)于1.5毫升螺帽离心管中在Mini-6TM(Hybraid，Ltd.，Middlesex，英国)杂交炉中42℃各自预杂交和杂交一小时。每次用1.5ml 1x SSC，0.01％十二烷基硫酸钠(SDS)42℃下洗涤15分钟，共进行3次，完成杂交后的洗涤。最终的洗涤在100毫升1x SSC(0.15M氯化钠，0.015M柠檬酸钠，pH7.2，Research Genetics)，0.01％SDS缓冲液(Sigma)中42℃下洗涤15分钟。在10毫升1xSSC缓冲液中进行最后漂洗。室温下空气干燥阵列约15-30分钟。室温下，将阵列与BiomaxTMMS或MR x-射线胶片(Eastman Kodak，Rochester，NY，美国)接触，进行放射自显影约0.5-4小时，直至获得期望的影像强度。制备显色的放射自显影照片。
使用标准技术试图在放射性标记的探针与从#1膜制备的阵列之间进行杂交。所有与阵列上适当的目标物质杂交的探针证明，DNA目标物质已结合到膜上，可用于探查，且这种探查可得到特异性的确定的杂交结果。
如下测试阵列的功能。使用互补于目标物质#1的放射性标记的DNA探针探查由膜#2制备的阵列。参考图15，可见所得放射自显影结果的照片。由此可见，探针与含有目标物质#1的阵列上三个区带之间发生杂交，与表示剩余15个DNA目标物质的其它45个区带的交叉杂交极小。因此，该阵列证明同时具有用于杂交研究的功能性和特异性。
然后，使用互补于目标物质#1和#7的放射性标记的DNA探针探查由膜#3制备的阵列。参考图16，可见所得放射自显影结果。由此可见，探针与阵列上六个区带之间发生杂交，与表示剩余14个DNA目标物质的其它42个区带的交叉杂交极小。
尽管参照特定的实施例，已十分详细的讨论了本发明，但其它实施方案也是可能的。因此，所附权利要求的范围不应局限于此处所描述的
优选实施方案的内容。

Claims (3)

1.一种制备高密度阵列的方法，包括将包含目标物质线的多个膜堆叠制成线束的步骤。
2.权利要求1的方法，其还包括将线束切割产生多个高密度阵列的步骤。
3.一种确证基因序列、检测遗传突变存在与否、定量或定性检测基因产物差异表达、绘制引发免疫应答的表位序列的图谱、或鉴定用于药物开发的化合物的方法，包括提供根据权利要求2的高密度阵列的步骤。
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