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1、小鼠表型分析国际合作计划,高翔南京大学模式动物研究所国家遗传工程小鼠资源库,小鼠基因功能百科全书,基础2002，小鼠基因组计划完1982，小鼠基因剔除技术资源国际合作2006，KOMP，EuCOMM NorCOMM，ChCOMM2008， 日本 KO program2009， 韩国 KO program2010， 台湾 KO program功能分析国际合作,基因功能,The availability of the full mouse genome sequence will immeasurably advance both the character and the pace of dis
2、covery.Nature 420, 515-516 (2002),人类重大疾病的动物模型：现代生物医药研发的核心条件基因组改造：建立疾病动物模型的核心技术小鼠等模式动物：开展基因组改造的最佳对象,2007年诺贝尔生理医学奖,Cappechi,Evans,Smithies,基因组改造转基因/基因剔除/诱发突变,肿瘤/代谢/心血管/免疫疾病（大、小动物结合）,疾 病 模 型,分子机理研究与医药研发,建立模型,分析与运用模型,Knockout Mouse Project ConsortiumNature Genetics 36, 921 (2004),North American Conditio
3、nal Mouse Mutagenesis project,The Texas A&M Institute for Genomic Medicine,European Conditional Mouse Mutagenesis Program,The Knockout Mouse Project,大规模小鼠突变：小鼠基因剔除国际联盟,CHCOMM，2006, MARC & MORCPB project, 2006, FudanAMMRA,测序(2002),IKMC(2006-11),IMPC(2012-22),独立实验室,大规模小鼠突变计划,1999 RIKEN GSC, ENU mutage
4、nesisPhenotype,Gene-driven1999 ANU, ENU mutagenesisPhenotype-driven2001Korea KITENU mutagenesisPhenotype-driven2002Fudai Unv. ICDpiggyBac transposon Phenotype-driven2004Academia Sinica, ENU mutagenesisPhenotype-driven2006 ChinaChCOMM2008, JAPANCARD,Osaka,Tokyo Univ.RIKEN BRC2009 Korea2010Taiwan,Asia
5、/Oceania,1997 MRC, GSFENU mutagenesisPhenotype-drivenGene-drivenEU EUCOMM Conditional Mutagenesis Program,2000 TMGC Jackson Laboratory Baylor College of Medicine McLaughlin Research Inst CMHDENU mutagenesisPhenotype-driven2006 NIH, KOMP2006 Genome CanadaNorCOMMNorth American Conditional Mouse Mutage
6、nesis project,Europe,US/Canada,ChemicalMutagenesis,Gene Targeting,May 2010,小鼠基因剔除计划进展,2005 ANU, Australian Phenomics Facility2001 Nanjing University MARC2003NLAC National Applied Research Laboratories2008 RIKEN BRCJapan Mouse Clinic2008Academia SinicaTaiwan Mouse Clinic2009GEM Korea Project2Korea Mo
7、use Metabolic Phenotyping Center,2002 NGFN-(FormeGSF) German Mouse Clinic (GMC)20042006 EUMORPHIAEUMORPHIA has developed a new robust primary screening platform for determining the phenotype of mice: EMPReSS slim2003 - MRCThe MRC Harwell Mouse Clinic 2006- ICS Institut Clinique de la SourisMouse Cli
8、nical Institute2007 EUMODIC EUMODIC undertake a primary phenotype assessment of mouse mutant lines developed in the EUCOMM2007 Sanger -Mouse Genetics Programme Phenotyping,1999 Jackson LaMPD (Mouse Phenome Project)2006US - BCM Mouse Phenotyping Core FacilityBaylor College of Medicine2007Deltagen and
9、 Lexicon 2007 CMHD- Toronto Centre for Phenogenomics phenotyping platfrorm,大规模小鼠模型分析与标准化项目,亚洲,欧洲,美/加,The goal of EUCOMM is to generate a collection of up to 13,000 mutated genes in mouse C57BL/6N ES cells using conditional gene trapping and gene targeting approaches.,KO mice,Database,SOP,Phenotyping
10、,EUMODIC undertake a primary phenotype assessment of up to 650 mouse lines derived from the EUCOMM project,Standardized Screens (EMPReSSlim),EUMORPHIA developed a robust primary screening platform for determining the phenotype of mice.,EuroPhenome is a open source projectto develop a software system
11、 for capturing, storing and analyzing raw phenotyping data,Archiving,“小鼠遗传学正在成为大科学计划，而目前这些国际计划只包括物理领域的大型强子碰撞型加速装置（LHC）和国际热核聚变实验堆计划（ITER）”。小鼠表型分析I期：5年9亿美金，4000小鼠品系。“No question, the mouse is where the action is”,动物模型分析,International Mouse Phenotyping ConsoritumRome 2007, Toronto 2008，2010,讨论议题 Feedin
12、g the pipelines模型来源及选择 Source/type of mutants, e.g. KO projects, CC, HS strains, ENU, etc Method of selection and coordination of selection of genes/linesProduction of mouse linesPhenotyping pipelines and Standardisation分析内容及标准化Multi-systems (primary) and system-focused (secondary) phenotyping Impro
13、vements and reducing animal numbersStandardisation and SOPsQuality control of released dataInformatics生物信息学Approaches to data capture Data annotation ontological developments and requirementsDatabases towards a federated structure with shared standardsData exchange, SOP description and ontologiesTec
14、hnology development技术开发Emerging new tests and platforms Improving the technology in existing tests raising efficiencies, reducing animal numbers and costs,KOMP 表型分析会议October 29-30 2009 Bethesda,目的 :讨论IKMC产出的小鼠的表型分析计划和战略决定：NIH 从2010-14年每年拨款$11M，共初步分析1000-1500个品系。讨论议题：基因选择 小鼠的生产分析方法和标准化 数据集成和利用,IMPC 现
15、状 现有 6个表型分析中心参加，预期最终全球10-12个 第一期 (2011-16) :准备和发展期 (分析 5,000 品系) 积极协调和发展多中心合作对IMPC的科学性、管理制度、管理结构做评估，于2016年推出全面实施计划 第二期 (20162021):完成基因功能诠释 (annotation),I M P C 战略 by Mark Moore,Ph.D ( IMPC Project Manager),Informatics（生物信息学）After meeting with groups from EUMODIC, the EBI, the JAX and discussions wit
16、h CASIMIR members, the emerging picture is to have a standalone database that will collect data from each centre and provide a user interface to the outside world.There have been significant efforts made by EuroPhenome and the Sanger groups to develop these tools but there is not sufficient critical
17、 mass in any one program to accomplish the level of complexity, data volume and number of tasks that will be required of the IMPC in the future.,I M P C 战略 by Mark Moore,Ph.D ( IMPC Project Manager),未来三年 (2010-2013) EUMODIC project will come to completion (500 lines). UCDavis will create and analyze
18、 312 KO mouse lines. WTSI will analyze 200 KO lines per year.TCP will produce and analyzes 100200 KO mouse lines per year. EUs INFRAFRONTIER is developing the vital infrastructure to continue and expand EU capacity. New centres at UAB (Barcelona) and the Czech Republic will be constructed and come o
19、nline NIH is raising fund of $22M per year for 5 years starting 2010,I M P C 战略 by Mark Moore,Ph.D ( IMPC Project Manager),20 phenotyping platforms 406 phenotype parameters155 metadata parameters,The Model of IMPC Informatics,Why the IMPCBuild a resource of KO mice and associated encyclopedia of gen
20、e functionsFree thousands of researchers from tool generationThis resource will be revolutionize research for the next 2030 yearsNovel genes will be brought to light that would otherwise be ignoredPotential for breakthrough discoveries,Regeneron 医药公司的药物开发链,I M P C Vision, JMC(Japan Mouse Clinic)RIKE
21、N BRC KMMPC(Korea Mouse Metabolic Phenotyping Center)KIST ,KRIBB, Souel Nat. Univ, Yoensei Univ. MARC ( Model Animal Research Center) Nanjin UniversityTMC (Taiwan Mouse Clinic) Academia Sinica NLAC (Nationa l Laboratory Animal Center),A large-scale Asian Mouse Phenotype Facilities,南京大学基因组改造和疾病模型研究平台
22、,完善的多种基因组改造技术平台BAC克隆转基因ENU化学诱变及筛选 国际水平基因剔除技术平台 BAC retrieval 技术构建打靶载体基于B6背景ES细胞的基因打靶100个条件性基因剔除/年(亚洲规模最大） 较完善的表型分析技术平台生物钟分析、代谢性疾病、心血管疾病、肿瘤等 新建100余种小鼠疾病模型品系,GEM Korea 2010 2014 (total 5 yrs)Phase I (3 yrs) + Phase II (2 yrs) = 15 millions /5 yrs,Dr. HJ Kim,Prof. JK Seong,Prof. GT Oh,Prof. HW Lee,Dr.
23、DY Yu,Prof. JH Park,Director,The Administration Organization of Taiwan Mouse Clinic,Mouse Clinic Phenotyping Workflow,1. Package of Neuroscience services: Modify-SHIRPA +homecage+open field+ rota-rod+hot/cold plate+tail flick+Von Frey (total 7 items)2. Package of Cardiovascular services: EKG+blood p
24、ressur+blood chemistry(TCHO, HDL-C, TG, CRP, Hb-W, CKMB)+CBC (total 9 items)3. Package of metabolism services: TSE test+metabolic cage+body fat+body lean+trabecular bone+2D X-ray (total 6 items)4. Package of liver function: GGT+AST+ALT+LDH+ALP+TBIL+TP+ALB+IP+D-BIL (total 10 items)5. Package of kidne
25、y function: BUN+CRE+UA+Ca+Mg+NH3-W+urine analysis (total 7 items),Database of SOPs in Japan Mouse Clinic (JMC),http:/www.brc.riken.jp/lab/bpmp/SOPs/,Wakana, S. et al. (2009) Introduction to the Japan Mouse Clinic at the RIKEN BioResource Center. Exp Anim., 58, 443-50.,All 27 SOPs that are included i
26、n JMC phenotyping pipelines,小鼠表型分析亚洲联盟BRC，2010.6,Phenotyping pipelines and StandardisationPrimary screen and in-depth screenStandardisation and SOPsBioinformaticsData exchange ex. phenotype, protocol?,Working committeeDiscussion pointPhenotyping pipelines and StandardisationPrimary screen and in-dep
27、th screenStandardisation and SOPsBioinformaticsData exchange ex.SDOPSymposiumAFLAS 4th Congress (Nov.11 2010, Taipei)“Trends in large-scale mouse phenotypyng program in Asia.”Standardization of mouse phenotypyng program and JMC Dr. Wakana (RIKEN BRC)Introduction of Korea mouse phenotyping program (T
28、entative) Dr. Seong (SNU)Introduction of China mouse phenotyping program (Tentative) Dr. Xiang Gao (Nanjin Univ.)Introduction of Taiwan mouse phenotyping program (Tentative) Dr. Yen (TMC)International integration of mouse phenotype information Dr. Masuya (RIKEN BRC),AMPC action plan,Our proposal for
29、 the sharing of mouse phenotyping protocols in AMPC,Acknowledgements,UK MRC Harwell,Steve BrownJohn HancockUniversity of CambridgePaul SchofieldThe Wellcome TrustMark MooreGermanyGerman Mouse Clinic, HelmholtzZentrumMartin Hrab de AngelisCanadaToronto Centre for Phenogenomics,Colin MakerlieTaiwanTai
30、wan Mouse Clinic, Academia Sinica, Jeffrey J.Y. YenNational Laboratory Animal Center Leo Wang, Si-TSE Jiang,USAMouse Knockout Project, NIHColin FlethcherUC Davis, University of CaliforniaKent LloydBaylor College of MedicineMonica JusticeKoreaSeoul National UniversityJe Kyung SeongKRIBB Ki-Hoan NamChinaIDT, Fudan UniversityXiaohui WuJapanRIKEN Yuichi ObataShigeharu WakanaCARD Kenichi Yamamura,
