CN1528880A - 用于制备固定化dna文库的装置，基因扩增的装置，温度控制方法以及系统比较基因的方法 - Google Patents

用于制备固定化dna文库的装置，基因扩增的装置，温度控制方法以及系统比较基因的方法 Download PDF

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CN1528880A
CN1528880A CNA2003101197536A CN200310119753A CN1528880A CN 1528880 A CN1528880 A CN 1528880A CN A2003101197536 A CNA2003101197536 A CN A2003101197536A CN 200310119753 A CN200310119753 A CN 200310119753A CN 1528880 A CN1528880 A CN 1528880A
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高桥浩二郎
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丹花通文
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Toyo Kohan Co Ltd
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Abstract

本发明涉及一种制备固定化的DNA文库的装置和基因扩增的装置，其可用于迅速地进行加热和冷却并相应地在短时间内进行热循环，并且也易于操作；本发明还涉及温度控制方法以及系统比较基因的方法。本发明的用于制备固定化DNA文库的装置包含一个反应器主体(10)，上面有凹进部分可以放置容器，一个盖子部分(50)放在上述反应器主体上方，以及由用于固定化DNA的基体(41)构成的容器(12)，其中该盖子部分(50)包含一个加热和冷却装置(51)和一个冷却装置(52)。在该装置中，计算机控制部分(64)将来自温度测量部分(61)的和程序表比较，且该计算机控制部分驱动加热/冷却(51)装置的温度控制部分(62)和冷却装置(52)的温度控制部分(63)。而且将多种DNA文库置入容器从而进行基因的系统比较。

Description

用于制备固定化DNA文库的装置，基因扩增的装置， 温度控制方法以及系统比较基因的方法
本申请是申请日为1999年2月8日的中国专利申请98804667.1的分案申请，原申请发明名称为“用于制备固定化DNA文库的装置，基因扩增的装置，温度控制方法以及系统比较基因的方法。”
工业领域
本发明涉及一种反应装置，它可通过加热少量的溶液应用于分子生物学和生物化学领域诸如基因工程，蛋白质工程，细胞工程，胚胎工程和免疫工程的多种反应。具体的，本发明涉及一种制备固定化DNA文库的方法，一种基因扩增的方法，一种系统比较基因的方法，以及因此的装置和固定化DNA文库。
本发明背景
常规地，聚合酶链式反应(PCR)已经广泛用作扩增基因的方法。在PCR方法中，将填充了反应溶液的管状塑料反应容器插入到铝块中并用盖子防止反应溶液的蒸发。铝块的温度周期性地按顺序变为热变性温度，退火温度和DNA合成温度。按预定次数重复这种温度控制循环。
但是，在常规PCR方法中，使用的设备是塑料反应器，它的热容量相对较大并且热传导率很低。此外，温度控制是对铝块本身进行操作。因而，需要花费更长的时间加热/冷却。由于反应溶液的温度控制不完全，复制的目的DNA的收量相对较低。
本发明的一个目的是解决上述缺陷和提供易于操作的，其中的加热/冷却步骤可快速操作并且可缩短反应热循环的基因扩增的装置，以及扩增基因的方法。
本发明的另一个目的是提供用于固定化DNA的基体和制备适于上述装置的固定化DNA的方法。
本发明的再一个目的是提供通过上述装置进行基因系统比较的方法。
本发明的公开：
本发明的制备固定化DNA文库的装置包括反应器主体，上面有凹槽部分来接纳容器；在反应器主体上方有一个盖子部分，含有加热/冷却装置和冷却装置。其中该装置的特征是容器由至少一种化学修饰的基体制成。
本发明的一种基因扩增的装置包括反应器主体，上面有凹槽部分来接纳容器；在反应器主体上方有一个盖子部分，含有加热/冷却装置和冷却装置。其中该装置的特征是容器至少由一种化学修饰的基体制成。
本发明的一种基因扩增的装置包括反应器主体，上面有凹槽部分来接纳容器；在反应器主体上方有一个盖子部分，含有加热/冷却装置和冷却装置。其中该装置的特征是容器至少由一种固定化了基因的基体制成。
在这些装置中，基体优选地是固相基体并且容器是可分离型的和盒型的。
在通过本发明的用于扩增基因的装置的温度控制的方法中，特征是将来自温度测量部分61的信号输入到计算机控制部分64，计算机控制部分64将信号与预先输入的程序表比较，从而驱动加热/冷却装置51的温度控制部分62以及冷却装置52的温度控制部分63。
本发明的固定化了DNA的基体的特征是该基体用于上述装置。
本发明的将基体冷冻保存的方法，特征是将固定化了DNA的基体冷冻保存。
本发明的系统比较基因的方法，特征是将多种固定化DNA-文库置入容器中。
附图的简要说明
图1图示了本发明的基因扩增装置的平面图，其中盖子是打开的。
图2是沿图1中的线A-A的剖面图。
图3是沿图1中的线B-B的剖面图。
图4图示制造容器的流程。
图5图示本发明的基因扩增装置的剖面图。
图6图示控制本发明的基因扩增装置的温度的方法。
图7图示产生固定化cDNA文库和扩增基因的流程。
图8图示产生固定化gDNA文库和扩增基因的流程。
实施本发明的最佳方式
下面描述本发明的基因扩增装置。
图1图示本发明基因扩增装置的平面图，其中盖子是打开的。图2图示本发明基因扩增装置的沿图1中的线A-A的横截面图。图3图示该装置的沿图1中的线B-B的横截面图。图4图示制造容器的流程。图5图示本发明的基因扩增装置的横截面图。
如图1至图3所示，数字10表示反应器主体，数字11表示在反应器主体上形成的凹槽部分。优选地，反应器主体10由化学稳定的聚合物材料诸如丙烯酸树脂和聚苯乙烯树脂组成。在反应器主体上至少制成一个凹槽部分11。凹槽部分的形状优选的是圆柱体或多边柱体诸如三角柱体和方柱体。优选地，容器12由热传导性好的基体41如金刚石基体，陶瓷基体诸如氮化铝和碳化硅以及金属基体诸如铝和不锈钢基体等制成。
或者，它优选地是一种金刚石样的碳基体，其部分由金刚石，碳基体和化合物基体组成。亦为优选的是塑料基体诸如聚碳酸酯基体和氟树脂基体。此外，优选地使用组合了上述基体的基体。
容器12可以有个底面部分，优选地易于安装到凹槽部分11和易于取下。
容器12优选地含有可分解为底面部分和侧壁部分的基体。例如，在方柱形容器时，基体可分为底面部分和四个侧壁部分。如图4(a)所示，各基体的每一边分别为从5mm至10mm，厚度大约0.1mm。如图4(b)所示，容器12可以是由底面部分43和侧壁部分44用合成树脂基体固定件42装配到一起(参见图4(c))。
这种情况下，优选地容器的底面部分或侧壁部分的至少其中之一，是由基因固定基体上而形成的。
另外，这些容器12可互相连接(盒型)，这样多个容器可以一次性置入多个凹槽部分11或取出，从而增进操作效率。在固定化DNA文库的描述中会详细描述这种盒型容器。
图5图示了本发明的基因扩增装置的横截面图。图5(a)图示反应容器10及在反应容器10上面的盖子部分50。图5(b)图示沿图5(a)中的线C-C的横截面图。在图5中，数字50，51和52分别表示盖子部分，加热/冷却装置和冷却装置。优选地，盖子部分由化学稳定的聚合物材料诸如丙烯酸树脂和聚苯乙烯树脂组成。
加热/冷却装置51是通过与容器12接触而加热/冷却容器12的装置。优选地，加热/冷却装置51是珀耳帖元件，电加热器，红外线灯等等。通过直接与容器12接触，可以直接控制容器12的温度。将传统扩增装置和本发明的装置比较，本发明的温度控制准确性是卓越的。冷却装置52中含有管道，其中有冷却剂或冷空气流动，或含有冷却风扇(fun)从而能够快速冷却容器12。
图6图示本发明的基因扩增装置的温控单元。在图6中，容器12的温度是根据温度测量部分61的信息通过加热/冷却装置51的温度控制部分62和冷却装置62的温度控制部分63来控制的。来自直接与容器12底部或侧壁部分接触的温度测量部分61的信号输入到计算机控制部分64。计算机控制部分64将输入信号和预先输入的程序表(温度增加速度，保持温度，保持时间，温度降低速度等等)比较。结果是驱动了加热/冷却装置51的温度控制部分62和冷却装置52的温度控制部分63。
实施方案
本发明的实施方案将参考图7和图8进行描述。对于容器12，金刚石片41(5mm×5mm，厚度0.1mm)用作金刚石基体。如图4所示，一个金刚石片用作底面部分，四个金刚石片用作侧壁部分。这些金刚石片与合成树脂基体固定件42组装在一起形成容器12。用作侧壁部分的金刚石片41是用有机羧酸化学修饰过的。组装好容器12后，将盖子部分50放到反应器主体10的上方。
(制备固定化DNA文库)
下面，参照图7和图8描述制备固定化DNA文库的实施例。首先，在mRNA(信使RNA)情况下，将寡dT16-20通过化学酯键反应固定到与容器12中的溶液接触的四个金刚石片41的表面上。在gDNA(基因组DNA)情况下，将含有目的的限制性酶位点的寡核苷酸通过化学酯键反应固定到金刚石片41的表面上(参见图7、图8)。构成容器12的四个金刚石片41是用有机羧酸化学修饰过的。为了固定化，将寡dT16-20的3’末端和寡核苷酸的5’末端与含有氨基的腺嘌呤(A)或胞嘧啶(C)或鸟嘌呤(G)联结。在图7和图8中，标记“ADC-R-”表示用有机羧酸化学修饰过的金刚石片。
接着，在cDNA(互补DNA)文库的情况下，从组织和细胞中提取含有mRNA的总RNA溶液，在0℃至4℃的低温条件下使mRNA与寡dT16-20杂交。杂交后，在37℃至60℃的适当的恒定温度下通过逆转录酶(RT)合成cDNA。此cDNA反应使用沿固定化寡dT16-20的末端5’端延伸反应而固定化了的。
将合成的固定化cDNA和mRNA的杂交溶液加热至90℃将mRNA脱杂交。然后，将反应溶液交换成Tris-EDTA(TE)缓冲液。在0℃至4℃的低温条件下再次用乙醇洗涤反应溶液。结果是，制备了单链DNA形式的纯化固定化DNA文库(参看图7)。
在gDNA文库情况下，类似寡dT16-20，将含有目的的限制性酶位点的固定化寡核苷酸(参看图8)固定到金刚石片41的表面。随后，将化学固定用反应溶液在0℃至4℃的低温下与含有杂交的寡核苷酸与限制性酶的反应溶液交换。与寡核苷酸杂交后，将反应溶液加热到37℃以进行半固定化寡核苷酸的限制性酶切割。
限制性酶切割后，再将反应容器在0℃至4℃的低温冷却。将反应溶液交换成含有用目的限制性酶片段化了的gDNA和连接酶的反应溶液。再将交换的溶液加热至37℃以进行连接酶反应。结果是，制备了单链DNA形式的gDNA文库(参看图8)。
可将制备在金刚石片表面的固定化cDNA文库或制备在金刚石片表面的固定化gDNA文库置入不同的容器，以便为了(1)至(3)的目的进行系统比较。
(1)比较多种样本的同种组织和细胞的基因变异。
(2)比较同一样本的各组织和细胞的基因生产和变异。
(3)比较同一样本的原始基因和药物治疗，手术(sergeant)等之后的基因的基因表达变化。
例如，在(1)的情况下，将多种样品(多种具有固定化DNA文库的金刚石片)置入不同的容器，以比较同种组织和细胞的基因变异。这些多个容器称为一个盒。这些盒安装到反应器主体。如果系统地制备两个或更多的盒，可以有效地比较多种样品。
本发明中，连接了多个容器的一个盒或多个盒作为一个聚集体。在聚集体的每个容器设置了固定化DNA文库，其定义为盒型固定化DNA文库。本发明中，这些盒型固定化DNA文库用于进行上述目的(1)和(2)的系统比较从而有效搜寻到基因的变异。
即使在使用或未使用PCR方法情况下，通过用TE缓冲液和乙醇溶液(70～75％)充分洗涤容器并将其冷冻和浸入乙醇溶液(100％)中保存，可以依照比较数据的要求等等半永久性的使用盒型固定化DNA文库。
(用固定化DNA文库扩增基因)
通过上述固定化cDNA或gDNA的盒型固定化DNA文库形成容器12的侧壁部分。用TE缓冲液充分洗涤容器12的内表面。将容器12的内面用TE缓冲液充分清洗后，装入与要扩增的DNA相关的引物并加入包含四种核苷酸及DNA聚合酶的PCR反应溶液。加入溶液后，将容器12依次将温度改变为热变性温度，用于将双链DNA分为单链DNA(95℃，大约1.5分钟)，变为退火温度，用于将单链DNA与DNA引物连接(45℃，大约1分钟)，以及变为DNA扩增温度，用于通过耐热的DNA聚合酶延伸DNA链(74℃，大约2分钟)。将这种温度控制重复30分钟以完成PCR方法(参看图7和图8)。为了相对短时间内一次进行多种样品的基因诊断，可提供一个系统，其中将用于制备盒型固定化DNA文库和扩增基因的必需数目的装置并列使用。例如，在50个样品的情况下，可将本发明的5个扩增基因的装置并列。
用于工业领域的机会
本发明的装置可在反应容器中快速加热和冷却反应溶液，这样可以在相当短的时间内扩增DNA。本发明的装置适用于自动基因诊断装置。在开发自动基因诊断装置时，最重要的技术问题是制备可以半永久性使用的盒型固定化文库和开发对基因扩增而言有卓越效率和特异性的的基因扩增装置。
由于PCR方法中制备文库的步骤的温度控制可通过相同的基体控制，通过提供高效自动盒型固定化DNA文库和最易于操作和最紧凑大小的基因扩增装置，可以解决上述两个问题。
也就是说，依照本发明的装置，除了直接控制DNA固定化反应的温度控制之外，使用金刚石片固定化文库可以直接控制扩增基因的温度控制。
依据本发明的装置，PCR反应溶液的温度控制可通过使用诸如高热传导率金刚石基体等基体直接控制，这样PCR方法的温度控制效率可以显著提高并可显著缩短所需的时间。此外，可以改进PCR效率诸如靶DNA的专一性扩增。
如果本发明的基体是高热传导率的，制备的固定化DNA文库变得十分稳定，因为金刚石基体相对于化学材料/溶液是稳定的，耐热性能是卓越的和辐射所致损伤小。一旦制备了盒型固定化DNA文库，就可以提供半永久性的多次重复使用的DNA文库。
通过利用金刚石基体的高热传导率，可将无化学修饰的金刚石基体等小片置入本发明的扩增装置，从而进行常规PCR方法的操作。

Claims (3)

1.一种基因扩增装置的温度控制方法，所述装置包括：
一个反应器主体，上面形成有其中安置容器的凹进部分，该容器包括合成树脂的固定件和在底面部分和四侧壁部分组合的5块基体；以及
一个放在上述反应主体上部的盖子部分，该盖子部分包含加热/冷却装置和冷却装置，
其中所述基体选自氮化铝、碳化硅、不锈钢、铝和金刚石样的碳，
其中在所述装置中，将来自温度测量部分61的信号输入计算机控制部分64，计算机控制部分61将输入信号和预先输入的程序表比较，然后驱动加热/冷却装置51的温度控制部分62和冷却装置52的温度控制部分63。
2.一种用于将固定化了DNA的基体冷冻保存的方法。
3.一种通过将多种DNA固定化文库置入容器进行基因的系统比较的方法。
CNA2003101197536A 1998-02-10 1999-02-08 用于制备固定化dna文库的装置，基因扩增的装置，温度控制方法以及系统比较基因的方法 Pending CN1528880A (zh)

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US6489111B1 (en) 2002-12-03
AU2187299A (en) 1999-08-30
CN1295613A (zh) 2001-05-16
KR20010040794A (ko) 2001-05-15
KR100653192B1 (ko) 2006-12-04
KR20060094541A (ko) 2006-08-29
CN1187445C (zh) 2005-02-02
KR100678978B1 (ko) 2007-02-06
EP1054056A4 (en) 2006-10-04
CA2320389A1 (en) 1999-08-19
KR20060094542A (ko) 2006-08-29
ID26228A (id) 2000-12-07
WO1999041362A1 (fr) 1999-08-19
KR100678980B1 (ko) 2007-02-06
AU747296B2 (en) 2002-05-16
KR20060094543A (ko) 2006-08-29

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