人类肿瘤的鼠模型网络入口鼠的肿瘤生物学数据库

1、.：.；人类肿瘤的鼠模型网络入口:鼠的肿瘤生物学数据库生命科学学院2002级生物技术 曹文瑞 学号:021402153摘要鼠的肿瘤生物学数据库MTB提供有遗传详细阐明(即先天性,转基因和有目的的突变种)的老鼠种群肿瘤遗传学和病理学的详细信息资源。这个数据库中的数据资源包括曾经发表的科学文献以及科学团体的直接的数据论据。研讨者利用基于环球网的讯问窗体访问MTB，他们可以利用这个数据库回答诸如“对基于C57BL/6J背景发明的转基因老鼠的肿瘤有哪些报道？，“老鼠中哪些肿瘤与Trp53 基因的突变有关？和“在不思索遗传背景的情况下，有哪些乳腺肿瘤的病理模型是可用的？之类的问题。鼠的肿瘤生物学数据库自

2、1998年在鼠基因组信息学网站( HYPERLINK )上提供运用。最近我们对MTB进展了一些改良，包括新的查询选项、重新设计的查询窗体和病理学及遗传学数据的结果界面、添加了病理学数据的电子数据论据和注解工具。导言实验室中老鼠曾经被用作研讨人类疾病的模型有很长时间了，这是由于他们在生理上、在基因组的容量和组织上与人类类似，并且易于在遗传上进展改造、易于实验操作。可以确切的反映人类癌症和组织病理学的发育中的鼠模型是1998年由国家癌症学会一次“偶尔的时机发现的。鼠模型提供了探求疾病进展过程中遗传及细胞方面的变化以及对有能够运用于临床的治疗战略进展测试的手段。不同的鼠纯系株在肿瘤易感性方面有很大不

3、同。规范的鼠纯系通常并不是人类肿瘤的恰当模型，这是由于鼠中零星肿瘤的低频率和较晚的发作时间。虽然如此，对特殊遗传背景下肿瘤特征方式的了解对于选择用于得到疾病进展方式更有利于建造人类特殊疾病的遗传及分子模型的转基因或靶突变的适宜鼠种系是重要的。许多关于有遗传详细阐明(即先天性,转基因和有目的的突变种)的鼠肿瘤易感性和抗性的数据在允许研讨者对不同鼠品系进展比较或比较规范鼠纯品系和基于同样先天背景建造的转基因或定点突变鼠品系癌症方式的方式下是不可用的。将连成一体的关于有遗传详细阐明的鼠品系遗传和病理生物学的不同数据放入一个可查询的数据库是MTB第一位的义务。在最近的一项对肿瘤遗传学研讨的网络资源的调

4、查中，我们发现了70余个与根底肿瘤遗传学研讨相关的数据库和信息资源。大多数现有肿瘤相关资源和数据库集中于单个基因或特殊的肿瘤性状。在我们调查的站点中，仅有少数提供关于人肿瘤鼠模型的信息；提供实验室老鼠病理生物学详细信息的站点那么更少。在提供有关肿瘤遗传学和病理学的综合数据的范围和深度上，MTB在现有的资源中是独一无二的。MTB自1998年以来就可以经过环球网方便的运用。出现于MTB中的最初数据是肿瘤类别、老鼠品系、遗传学、病理学和参考文献已发表和未发表的文献都包含于这个数据库中。这些方面代表了查询此数据库的基于网络的窗体的主要内容。MTB是用于描画由Jackson实验室鼠基因组信息MGI组织建

5、立的实验室老鼠品系遗传及生物学信息的信息学下部构造的延伸。MTB中鼠基因和品系的命名法于鼠基因数据库( HYPERLINK /mgihome/nomen /mgihome/nomen)描画的鼠的正式命名法。数据库中运用的解剖学术语于基因表达数据库GXD鼠解剖学控制性词汇。MTB中的许多病理学和诊断学术语于一本权威的教科书衰老鼠的病理学。2000年对MTB的改良关于MTB的设计和实施细节已在别处引见。这篇报告的目的是引见MTB的新特征和对它的改良。我们在过去一年我们收到的数据库运用者的最普遍的意见是提供额外的查询选项和对病理学及遗传学数据的报道。运用者还要求我们重新设计一些数据摘要页面以便使他们

6、不用经过如此多的超文本链接得到他们想要的信息。根据用户反响意见而作出的对系统的改动细节将在下面进展阐明。对这些变化进展阐明的网络链接可以在本文的在线版本中看到增补资料。肿瘤类型查询的新查询选项我们实现了对肿瘤类型查询选项两个方面的改良。首先，我们添加了经过解剖学体系而不仅仅是器官称号查询数据库的才干。运用者如今可以提交如“从MTB中找到一切消化系统肿瘤的信息之类的查询。第二，我们添加了对基于肿瘤转移形状查询限制的支持。例如，如今搜索知的分散到肺或肝脏的乳腺瘤成为能够。对病理学查询的改良在早先的MTB版本中，运用者可以仅仅查询和查看特殊的种/肿瘤结合的显微照片和诊断记录例如，“显示一切FVBN-

7、TgN(MMTVPyVT)634Mul雌性转基因鼠的乳腺癌种类。在2000年十月的数据库版本中，我们添加了新的查询窗体允许运用者用更加普通规范包括器官称号如“找到一切物种的肝脏肿瘤的病理学图像、品系称号如“找一切可用的BALB/c品系一切器官系统和一切类型的肿瘤和肿瘤类型如“找一切可用的一切物种的乳腺癌病理学数据搜索病理学数据。经过这项改良，数据库运用者可以在MTB中经过一项查询产生关于病理学数据广泛查询的结果而不用需一次找一个肿瘤/品系组合。MTB中对病理学数据陈说的第二项改良与对组织学图像的显示相关联。在早先的数据库版本中，运用者需求在病理学摘要页面用鼠标点击一个组织学图像极小的版本来查看

8、一个对细胞容颜有更高分辨率的图像。具有更高分辨率图像会替代当前窗口，运用者不能再对图像和为图像提供的诊断正文进展比较。我们实现了对这种进退两难的局面的简单处理方法，运用者可以经过用鼠标点击一个位于极小版本的显微图片下方的标有“查看更大图片的按钮在一个独立窗口中查看更高分辨率的图像和诊断正文。这个显示更高分辨率图像的独立窗口可以调整大小、可以独立于网站主页而封锁。对基因查询的改良在MTB数据库的概念和逻辑设计中，我们过去把肿瘤细胞中遗传改动的概念从与某一特定品系老鼠的背景相关的遗传学中分别出来。结果，对MTB中品系查询和以基因称号或符号表示的肿瘤查询都感兴趣的用户需求用两种不同的查询窗体进展搜索

9、。我们实现了一种允许用户用基因符号同时搜索品系和肿瘤信息。例如，用基因符号在MTB中搜索眼癌1Rb1基因可以得到带有靶突变，诱发突变或是自然突变的Rb1基因的品系的信息和已报道的在Rb1基因中发生遗传改动如点突变，缺失等的肿瘤的信息。基因符号的查询结果以两部分被前往。首先，MTB中所记录的基因的等位基因列表被前往。第二，这些等位基因与肿瘤和/或品系的联络会连同适当详细页面的超文本链接一同显示。对肿瘤发生频率表格的改良MTB肿瘤发生频率表格作为查询和显示鼠纯系株家族复杂的癌症方式信息的图表手段于1999年提出的。肿瘤发生频率表格包括大多数作为以建立通常运用和遗传上多样的实验室鼠纯系的根本表形数据

10、为目的的广泛国际协作也称为鼠“表型组的一部分被系统描画的鼠纯系株。我们对肿瘤发生频率表格做了两项改良以使它为我们的用户提供更多的信息。首先，我们将表格从用三色编码反映肿瘤发生频率的系统变为五色编码系统。五种颜色的显示方式为用图表交流肿瘤发生频率提供了更加准确的信息，还有一个额外的益处，就是即使图表以黑白方式打印或显示也容易区分它们的相对发生频率。第二，我们对表格中的种系清单进展了重新构造，使它们由以字母顺序排序变为以纯系株的系谱关系分组。这种组织方式使寻觅预期在肿瘤易感性方式比较类似的种系。病理学信息的电子数据论据：JaxPathMTB最初获得信息的方式是经过肿瘤生物学和鼠遗传学方面的专家级生

11、物学家对已发表科学文献的进展定期回想。为了给病理学信息提供电子论据和共有的查询方法，我们发明了一个从MTB主页容易进入的基于网络的数据库JaxPath。JaxPath允许用户向MTB提交未发表的病理学图像和数据，或者或者添加由于空间或费用缘由而没有包含于初始发表文章之内的增补图像。向JaxPath提交数据的运用者会被分配一个允许他们经过网络对投稿的阐明和注解进展编辑的密码。对投稿者图片和注解的援用会在网站的病理学数据摘要中显示。利用MTB进展查询ID的添加就像在以前的一篇MTB的报告中提到的那样数据库中每一肿瘤的实例都以肿瘤称号、品系、性别和肿瘤来源器官的组合进展描画的。MTB中这种组织信息的

12、方式反映了我们的遗传背景在肿瘤发生方式中发扬重要作用的根本想象。MTB中每一肿瘤实例都被自动分派到一个允许我们明白无误地指定该肿瘤并建立通往其它数据库的稳定链接的标识符这些添加的标识符在许多查询结果页面中显示中。曾经在他们感兴趣经过常规方法进展查询的数据库中鉴别出特定记录的运用者如今可以可用适宜的MTB新增ID直接查询MTB。未来研讨方向国家肿瘤学会最近成立了人类肿瘤鼠模型协会MMHCC，并把它作为加速人肿瘤鼠模型建立和完成肿瘤称号和诊断术语一致命名法的机构。MMHCC正在建造一个将包括关于治疗药物检测和在MTB范围以外的实验草案信息的人肿瘤鼠模型数据库，虽然它如今还不易为公众运用。由于许多将

13、在MMHCC中描画的鼠品系也将在MTB中有所记录，未来一年我们数据库小组的一个组要义务就是将MTB衔接到MMHCC。这两个数据库的综合将允许用户无过失地从根本癌症表型和遗传信息转向详细记述的临床前和临床鼠模型、实验草案和治疗实验结果。参考文献1 Paigen,K. (1995) A miracle enough: the power of mice. Nature Med., 1, 215220. HYPERLINK /cgi/external_ref?access_num=A1995QX55900026&link_type=ISI ISI HYPERLINK /cgi/external_re

14、f?access_num=7585036&link_type=MED Medline 2 DePinho,R.A. and Jacks,T. (1999) Mouse models of cancer: Introductory comments. Oncogene, 18, 5248. HYPERLINK /cgi/external_ref?access_num=000082808400001&link_type=ISI ISI 3 Klausner,R. (1999) Studying cancer in the mouse. Oncogene, 18, 52495252. HYPERLI

15、NK /cgi/external_ref?access_num=000082808400002&link_type=ISI ISI HYPERLINK /cgi/external_ref?access_num=10498876&link_type=MED Medline 4 Bult,C.J., Krupke,D.M. and Eppig,J.T. (1999) Electronic access to mouse tumor data: the Mouse Tumor Biology Database (MTB) project. NucleicAcids Res., 27, 99105.

16、HYPERLINK /cgi/ijlink?linkType=ABST&journalCode=nar&resid=27/1/99 Abstract/Free FullText 5 Bult,C.J., Krupke,D.M., Sundberg,J.P. and Eppig,J.T. (2000) Mouse Tumor Biology Database (MTB): enhancements and current status. Nucleic Acids Res., 28, 112114. HYPERLINK /cgi/ijlink?linkType=ABST&journalCode=

17、nar&resid=28/1/112 Abstract/Free FullText 6 Bult,C.J., Krupke,D.M., Tennent,B.J. and Eppig,J.T. (1999) A survey of web resources for basic cancer genetics research. Genome Res., 9, 397408. HYPERLINK /cgi/ijlink?linkType=FULL&journalCode=genome&resid=9/5/397 Free FullText 7 Blake,J.A., Eppig,J.T., Ri

18、chardson,J.E., Kadin,J.A., Bult,C.J. and the Mouse Genome Database Group. (2001) The Mouse Genome Database (MGD): Integration Nexus for the Laboratory Mouse. Nucleic Acids Res., 29, 9194. HYPERLINK /cgi/ijlink?linkType=ABST&journalCode=nar&resid=29/1/91 Abstract/Free FullText 8 Ringwald,M., Eppig,J.

19、T., Kadin,J.A., Richardson,J.E. and the Gene Expression Database Group. (2000) GXD: a gene expression database for the laboratory mouse: current status and recent enhancements. NucleicAcids Res., 28, 115119. Updated article in this issue: Nucleic Acids Res. (2001), 29, 98101. HYPERLINK /cgi/ijlink?l

20、inkType=ABST&journalCode=nar&resid=28/1/115 Abstract/Free FullText 9 Mohr,U., Dungworth,D.L., Capen,C.C., Carlton,W.W., Sundberg,J.P. and Ward,J.M. (1996) Pathobiology of the Aging Mouse. International Life Science Institute, Washington, DC, USA, vols 1 and 2. 10 Paigen,K. and Eppig,J.T. (2000) A mo

21、use phenome project. Mamm.Genome, 11, 715717. HYPERLINK /cgi/external_ref?access_num=000089003800001&link_type=ISI ISI HYPERLINK /cgi/external_ref?access_num=10967127&link_type=MED Medline 11 Beck,J.A., Lloyd,S., Hafezparast,M., Lennon-Pierce,M., Eppig,J.T., Festing,M.F.W. and Fisher,M.C. (2000) Gen

22、ealogies of mouse inbred strains. Nature Genet., 24, 2325. HYPERLINK /cgi/external_ref?access_num=000084609200010&link_type=ISI ISI HYPERLINK /cgi/external_ref?access_num=10615122&link_type=MED MedlineWeb-based access to mouse models of human cancers: the Mouse Tumor Biology (MTB) Database Carol J.

23、Bult HYPERLINK /cgi/content/full/29/1/95 l FN1#FN1 *, Debra M. Krupke, Dieter Nf, John P. Sundberg and Janan T. Eppig The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA Received October 3, 2000; Accepted October 4, 2000. ABSTRACTThe Mouse Tumor Biology (MTB) Database serves as a cura

24、ted, integrated resource for information about tumor genetics and pathology in genetically defined strains of mice (i.e., inbred, transgenic and targeted mutation strains). Sources of information for the database include the published scientific literature and direct data submissions by the scientif

25、ic community. Researchers access MTB using Web-based query forms and can use the database to answer such questions as What tumors have been reported in transgenic mice created on a C57BL/6J background?, What tumors in mice are associated with mutations in the Trp53 gene? and What pathology images ar

26、e available for tumors of the mammary gland regardless of genetic background?. MTB has been available on the Web since 1998 from the Mouse Genome Informatics web site ( HYPERLINK ). We have recently implemented a number of enhancements to MTB including new query options, redesigned query forms and r

27、esults pages for pathology and genetic data, and the addition of an electronic data submission and annotation tool for pathology data. INTRODUCTION The laboratory mouse has long served as an important animal model for human disease because it is known to resemble humans physiologically, is highly si

28、milar to humans in both genome content and organization, is well characterized genetically and is easily manipulated experimentally ( HYPERLINK /cgi/content/full/29/1/95 l GKE019C1#GKE019C1 1). Developing mouse models that accurately reflect the genetics and histopathology of human cancers was recog

29、nized in 1998 as an exceptional opportunity by the National Cancer Institute ( HYPERLINK ) ( HYPERLINK /cgi/content/full/29/1/95 l GKE019C2#GKE019C2 2). Mouse models provide the means to explore genetic and cellular aspects of disease progression and to test therapeutic strategies that might ultimat

30、ely be used clinically in humans ( HYPERLINK /cgi/content/full/29/1/95 l GKE019C2#GKE019C2 2, HYPERLINK /cgi/content/full/29/1/95 l GKE019C3#GKE019C3 3). Different inbred strains of mice vary in their intrinsic tumor susceptibility. Standard inbred mice are not usually appropriate models for human c

31、ancers because of the relatively low frequency and late onset of sporadic cancers in mice. However, knowing the characteristic cancer profile of a particular genetic background is critical to the process of selecting the appropriate mouse strain for developing transgenic or targeted mutation mice wh

32、ose disease progression patterns may be more useful for modeling genetic and molecular aspects of a specific human disease. Much of the data about tumor susceptibility and resistance in genetically defined strains of mice (i.e., inbred lines, transgenics, targeted mutation strains) are not available

33、 in a format that allows researchers to compare different strains of mice to one another or to compare the cancer profile of a standard inbred strain to that of a transgenic or targeted mutation line created on the same inbred background. Integrating diverse data about genetics and pathobiology for

34、genetically defined strains of mice in a queryable database system is the primary mission of the Mouse Tumor Biology (MTB) Database ( HYPERLINK /cgi/content/full/29/1/95 l GKE019C4#GKE019C4 4, HYPERLINK /cgi/content/full/29/1/95 l GKE019C5#GKE019C5 5). In a recent survey of Web-based resources for c

35、ancer genetics research, we identified over 70 databases and information resources related to basic cancer genetics research ( HYPERLINK /cgi/content/full/29/1/95 l GKE019C6#GKE019C6 6). The majority of existing cancer-related resources and databases focus on single genes or specific cancer syndrome

36、s. Only a handful of the sites we surveyed provided information about mouse models of human cancers; even fewer sites provided detailed information about the pathobiology of laboratory mice. The MTB Database is unique among existing resources in both its scope and degree of integration of data about

37、 cancer genetics and pathology in laboratory mice. The MTB Database has been accessible via the World Wide Web since 1998 ( HYPERLINK /cgi/content/full/29/1/95 l GKE019C5#GKE019C5 5). The primary data types represented in MTB are tumor types, mouse strain, genetics, pathology and references (both pu

38、blished and unpublished references are included in the database). These areas, in turn, represent the main Web-based forms that are used to query the database. MTB is an extension of the informatics infrastructure developed for representing genetic and biological information about the laboratory mou

39、se established by the Mouse Genome Informatics (MGI) Group at The Jackson Laboratory ( HYPERLINK ). The nomenclature used in MTB for genes and strains of mice comes from the official mouse nomenclature represented in the Mouse Genome Database ( HYPERLINK /mgihome/nomen /mgihome/nomen) ( HYPERLINK /c

40、gi/content/full/29/1/95 l GKE019C7#GKE019C7 7). Anatomical terms used in the database come from a controlled vocabulary of mouse anatomy supported by the Gene Expression Database (GXD) ( HYPERLINK /cgi/content/full/29/1/95 l GKE019C8#GKE019C8 8). Much of the pathology and diagnostic terminology used

41、 in MTB comes from the Pathobiology of the Aging Mouse ( HYPERLINK /cgi/content/full/29/1/95 l GKE019C9#GKE019C9 9), a standard mouse pathology text. ENHANCEMENTS TO MTB IN 2000Details concerning the design and implementation of MTB have been described elsewhere ( HYPERLINK /cgi/content/full/29/1/95

42、 l GKE019C4#GKE019C4 4, HYPERLINK /cgi/content/full/29/1/95 l GKE019C5#GKE019C5 5). The purpose of this report is to describe new features and recent enhancements to MTB. The most common input we received from our database users during the past year was to provide additional query options and report

43、s for pathology and genetic data. Users also requested that we redesign some of the data summary pages so that they did not have to follow as many hypertext links to retrieve the information they were seeking. The details of the changes to the system in response to user feedback are described below.

44、 Screen shots and web links illustrating these changes can be viewed in the online version of this article (Supplementary Material). New query options for tumor type searchesWe have implemented two enhancements to the query options for tumor types. First, we added the capacity to search the database

45、 by anatomical system instead of just by organ name. Users can now submit queries such as Retrieve all information from MTB for tumors of the Digestive System. Second, we added support for constraints on queries based on the status of metastases of a tumor. It is now possible, for example, to search

46、 for tumors of the mammary gland that are known to metastasize to the lung or the liver. Enhancements to pathology queriesIn the previous versions of MTB, users could only query for and view photomicrographs and diagnostic descriptions for specific strain/tumor combinations (e.g., Show me all mammar

47、y gland adenocarcinomas for FVBN-TgN(MMTVPyVT)634Mul female transgenic mice). In the October 2000 release of the database, we added new query forms to allow users to search for pathology data by more general criteria, including organ system (e.g., Retrieve all pathology images for tumors of the live

48、r regardless of strain), strain name (e.g., Retrieve all available pathology images for tumors in BALB/c mice regardless of organ system or type of tumor) and tumor type (e.g., Retrieve all available pathology data for mammary gland adenocarcinomas regardless of strain). With this enhancement, datab

49、ase users can now generate results for broad queries about the pathology data in MTB with a single query instead of having to retrieve tumor/strain combinations one at a time. A second enhancement to the representation of pathology data in MTB relates to the display of the histology images themselve

50、s. In previous versions of the database, users would mouse click on a thumbnail version of the histology images in a pathology summary page to view a version of the image with higher resolution of the cellular features. The higher resolution image replaced the current window and the user could no lo

51、nger compare the image with the diagnostic text provided for the image. We have implemented a simple solution to this dilemma in which the user can view the higher resolution image and diagnostic text in a separate window by mouse clicking on a button labeled View Large Image that is below the thumb

52、nail version of the photomicrograph. The separate window displaying the higher resolution image can be resized and closed independently of the main web page. Enhancements to gene queriesIn both the conceptual and logical design of the MTB database we separated the concepts of genetic changes in tumo

53、r cells from the genetics associated with the background of a particular strain of mouse. As a result, users interested in querying both strains and tumors represented in MTB by gene name or symbol needed to search the database using two different query forms. We have implemented a new query mechani

54、sm that allows users to search strain and tumor information by gene symbol simultaneously. Now, for example, a search of MTB using the gene symbol for the retinoblastoma 1 gene (Rb1) will return information both on the strains that carry a targeted, induced or spontaneous allele of the Rb1 gene, as

55、well as on the tumors that have reported genetic alterations (e.g.,point mutations, deletions, etc.) in the Rb1 gene. The query results for gene symbol searches are returned in two parts. First, a list of the alleles for genes represented in MTB is returned. Second, the associations of the alleles w

56、ith either tumor and/or strains are indicated along with hypertext links to the appropriate detail pages. Enhancements to the tumor frequency gridThe MTB tumor frequency grid was introduced in 1999 as a graphical means of querying and displaying complex cancer profile information for families of inb

57、red strains of mice ( HYPERLINK /cgi/content/full/29/1/95 l GKE019C5#GKE019C5 5). The tumor frequency grid includes most of the inbred strains of mice that are being systematically characterized as part of an international collaboration (also known as the mouse phenome project) to establish broad ba

58、seline phenotypic data on commonly used and genetically diverse inbred strains of the laboratory mouse ( HYPERLINK /cgi/content/full/29/1/95 l GKE019C10#GKE019C10 10). We have made two enhancements to the tumor frequency grid to make it more informative for our users. First, we changed the grid from

59、 a three-color coding system to reflect tumor frequency to a five-color system. The display of five colors allows more precise information about tumor frequency to be communicated graphically and has the additional benefit that relative frequencies can be discerned even if the grid is printed out or

60、 displayed in black and white. Second, we re-structured the listing of the strains in the grid from an alphabetical order to groupings that are associated with the genealogical relationships of the inbred strains ( HYPERLINK /cgi/content/full/29/1/95 l GKE019C11#GKE019C11 11). This organization make