13 ZHAO, Deming - English

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1 动物传染性海绵状脑病报告人 : 赵德明教授单位 : 中国农业大学国家动物海绵状脑病实验室

2 What are TSEs? content Encephalopathy Status of TSEs Pathogen? important biological characteristics of prions Strains and Species Barrier Pathogenesis? Our research work on TSEs

3 What are TSEs? TSEs are a class of chronic, progressive, neurodegenerative disease

4 What are TSEs? Pathology of TSE spongiform change, neuronal loss, amyloid or protein fibrils formation. Scrapie Coloured TEM of scrapie fibres

5 What are TSEs? TSEs types Humans Creutzfeldt-Jakob Disease (naturally occurring) CJD,1920/1921 New Variant Creutzfeldt-Jakob Disease (causally related to BSE) nvcjd vcjd,1996 Other rare forms Kuru Fatal familial insomnia GSS(Gersstmann-Straussler- Scheinker) disease

6 What are TSEs? Animals ---Cattle BSE, Mad Cow, Sheep/Goats Scrapie, Deer/Elk Chronic Wasting Disease,CWD, Feline Feline spongifrom encephalopaphy,fse, Mink Transmissible mink encephalopathy,tme,1967

7 What are TSEs? Several important human and animal TSEs Disease name Natural host Transmission 克雅氏病 (Creutzfeldt Jakob disease,cjd) Humanity Genetic, iatrogenic 变异型克雅氏病 (variant CJD, vcjd) cow Ingestion 格斯特曼综合症 (Gerstm Straussler Scheinker disease,gss) Humanity Geneti 库鲁病 (Kuru disease) Humanity Ingestion 致死性家族性失眠症 (Fatal familial insomnia,ffi) Humanity Geneti 羊瘙痒症 (Scrapie) Sheep, goats Ingestion 牛海绵样脑病 (BSE) cow Ingestion 鹿慢性消耗性疾病 (chronic wasting disease) deer Ingestion 猫科动物海绵样脑病 (Feline spongiform encephalopathy) cat Ingestion 传染性水貂脑病 (Transmissible mink encephalopathy) mink Ingestion

8 Encephalopathy Status of TSEs

9 Encephalopathy Status of TSEs 羊痒病 (Scrapie) epidemiology England,1732 Europe, the Middle East, Japan, Canada, the United States, Kenya, South Africa, Colombia and parts of Asia hazard precaution VRQ/VRQ susceptible ARR/ARR resistant

10 Encephalopathy Status of TSEs 疯牛病 (BSE) epidemiology United Kingdom,1986 outbreak,from 1993, origin of a disease:mbm hazard precaution

11 Global mad cow cases map Dark green areas are countries with confirmed human cases of vcjd. Light green shows countries which have reported cases of only BSE.( 2008) From Wikipedia, the free encyclopedia

12 Bovine Spongiform Encephalopathy Status oie members Negligible BSE risk Argentina Iceland Paraguay Australia India Peru Chile New Zealand Singapore Denmark Norway Sweden Finland Panama Uruguay According to RESOLUTION No.17(79th General Session May 2011)

13 Bovine Spongiform Encephalopathy Status oie members Controlled BSE risk Austria Greece Mexico Belgium Hungary Netherlands Brazil Ireland Poland Canada Italy Portugal Chinese Taipei Japan Slovak Republic Colombia Korea (Rep. of) Slovenia Cyprus Latvia Spain Czech Republic Lichtenstein Switzerland Estonia Lithuania United Kingdom France Luxembourg United States of America Germany Malta

14 The Human TSEs 库鲁病 (Kuru disease) 克 - 雅氏病 (CJD) (vcjd) 变异型克雅氏病 - vcjd victim Michael (Steven Helliwell) and doctor Saira (Krupa Pattani)

15 vcjd first described in March 1996; strongly linked to BSE.

16 Country 截止 2010 年全球 BSE 与 vcjd 的发病情况 BSE cases vcjd cases Country BSE cases vcjd cases Austria 5 0 Israel 1 56 Belgium Italy Canada 17 1 Japan 26 1 Czech Republic 28 0 Liechtenstein 2 0 Denmark 14 0 Luxembourg 2 1 Falkland Islands 1 0 Netherlands 85 3 Finland 1 0 Oman 2 0 France Poland 21 0 Germany Portugal Greece 1 0 Saudi Arabia 0 1 Hong Kong 2 0 Slovakia 15 0 Republic of Ireland 1,353 4 Slovenia 7 0 Sweden 1 0 Spain Switzerland United Kingdom 183, Thailand 0 2 United States 3 3 Total 188,

17 Pathogen and Pathogenesis?

Nobel Prize to Gajdusek 1955-1957: Discovery of Kuru in Papua New Guinea

18 Nobel Prize to Gajdusek : Discovery of Kuru in Papua New Guinea : Transmition of Kuru to chimpazees 1976: Nobel Prize to Gajdusek

Nobel Prize to Prusiner 1980: Prion, the proteinaceous

all mammals 1992: Knock-out of prion gene in mice

between PrPc and PrPsc 1997: Nobel Prize to Prusiner

19 Nobel Prize to Prusiner 1980: Prion, the proteinaceous infectious agent of scrapie 1985: The prion gene in all mammals 1992: Knock-out of prion gene in mice resulted in resistance 1993: Structureal differences between PrPc and PrPsc 1997: Nobel Prize to Prusiner Prion Protein-only-Hypothesis The hypothesis is confirmed in 2010

20 What are Prions? PrP C Prion(PrP SC )

21 Properties of the cellular and the infectious form of the prion protein PrPC PrPSc solubility soluble non soluble structure predominantly alpha-helical predominantly beta-sheeted multimerisation state monomeric multimeric (aggregates) infectivity non infectious infectious Resistance to PK no yes

22 Strains and Species Barrier

23 Strains (Strains model, Collinge, 2007)

24 Species Barrier Very easy easy difficult

25 Species Barrier is not absolute CJD 人 PRNP vcjd WT mouse

26 Information of Strains and Species Barrier is encoded by prions conformations,not by PrP primary structure.

27 The Pathogenesis of PrPSc Invasion of peripheral Shift CNS Infection and replication in peripheral transfer from peripheral to central. Way? Infection and eventually lead to neurodegene ration in CNS

28 How to from one cell to another cell? PrP SC PrP C (c) Infected cell Normal cell

29 Our research work on TSEs National TSE detection tasks Basic theory studies and new diagnostic techniques of TSEs and bovine tuberculosis

一.National TSE detection tasks 1 BSE testing date 2003-2004 2004-2005 2005-2006 2006-2007 2007-2008 2008-2009 2009-2010 quantity 616

30 一.National TSE detection tasks 1 BSE testing date quantity Total Scrapie testing date quantity Total 5677

31 National TSE detection tasks we have conducted on-site visits and research on pastorals of some provinces in northern China in 2003 and Visited eight sheep farm, 60 flocks about 31,000 sheep. Found 813 suspected cases of sheep scrapie. These suspected cases were detected in laboratory, 85 shows pathological changes of scrapie. Immunohistochemistry and Western blot analysis showed that 31 cases of samples positive signal.

32 Visits to the investigation in the pastoral

33 Concentrate feeding and observation

34 sample collection

35 Laboratory testing,histopathological observation of the sheep brain 正常羊脑干英国 VLA 提供的标准样品 Histopathology results Histopathology results

36 Immunohistochemistry Western blot

37 1 Gene polymorphism Incubation period, susceptibility, the species barrier with the PRNP polymorphisms 19 kinds of animal prion protein gene (PRNP) Cloning, subcloning 1.Virus Genes, 2005, 30: ;2.Virus Gene : ;3. Virus Research : 93-96

38 2 Scrapie Research Domestic sheep genotyping scrapie susceptibility closely related to the 136,154,171 amino acid polymorphisms Resistance A:R:R: 10% Moderate A:R:Q: 80% Highly susceptible V:R:Q: 0% The others A:R:K: 10%

3 Conformational conversion of prion protein in

Conformational change in prion protein research is

transformation of PrPc and PrPsc, to explore the

39 3 Conformational conversion of prion protein in vitro and molecular mechanisms of regulation Conformational change in prion protein research is the basis of TSE study Around the dynamic transformation of PrPc and PrPsc, to explore the ph and copper ions on the recombinant PrP structural change effects.

40 4 Pathogenic features, Replication,and the relationship between the host cell

41 OD 值 5 Sheep recombinant PrPc protein monoclonal antibodies and Western-blot diagnostic kit developed D11 原液 1:1000 1:2000 1:4000 1:8000 1:16000 细胞上清 SP2/ :1000 1:2000 1:4000 1:8000 1: :32000 腹水 SP2/0 Hybridoma supernatant titer Ascites monoclonal antibody titer

42 43KD 31KD 20KD 14.4KD specific identification of Westernblot

TSE 相关文章在国内外期刊发表 TSE 相关论文 80 余篇, 其中在国外期刊发表 30 余篇近期发表的 TSE 相关 SCI 文章 1. Junwen Qiao,Xiaoou Su,Yiqin Wang,Jianmin Yang,Mohammed Kouadir, Xiangmei Zhou, Xiaomin Yin,Deming Zhao*.

43 TSE 相关文章在国内外期刊发表 TSE 相关论文 80 余篇, 其中在国外期刊发表 30 余篇近期发表的 TSE 相关 SCI 文章 1. Junwen Qiao,Xiaoou Su,Yiqin Wang,Jianmin Yang,Mohammed Kouadir, Xiangmei Zhou, Xiaomin Yin,Deming Zhao*.Cloning and characterization of full-length coding sequence (CDS) of the ovine 37/67-kDa laminin receptor (RPSA). Molecular Biology Reports. (2009) 36: Haiyun Zhou1, Xiangmei Zhou 1,Mohammed Kouadir, Zhongqiu Zhang, Xiaomin Yin,Lifeng Yang,, Deming Zhao, Induction of Macrophage Migration by Neurotoxic Prion Protein Fragment.Journal of Neuroscience Methods. 2009,181: J. E. Zhang, B. Sun, W. Y. Pang, J. W. Qiao,M. Kouadir, L. F. Yang* and D. M. Zhao* Polymorphisms of the prion protein gene (PRNP) in the Tibetan Mastiff.Animal Genetics. 2009,10:

44 4. Yiqin Wang, Zhenkui Qin, Yonggan Bao,Junwen Qiao,Lifeng Yang*,Deming Zhao*. Sequence analysis of the prion protein gene in Mongolian gazelles(procapra gutturosa).virus Genes.2009,39: Jun Wen Qiao, Xiao Ou Su, Yu Xing Li, Jian Min Yang, Yi Qin Wang, Mohammed Kouadir, Xiang Mei Zhou,Li Feng Yang, Xiao Min Yin,De Ming Zhao*.Variable levels of 37/67-kda laminin receptor (RPSA) mrna in ovine tissues: potential contribution to the regulatory processes of PrPSc propagation? Animal Biotechnology. 2009,20: GuihuaWang1, Xiangmei Zhou1, Yu Bai, Zhongqiu Zhang, and Deming Zhao* Cellular prion protein released on exosomes from macrophages binds to Hsp70. Acta Biochim Biophys Sin 2010, 42: Cai-Xia Han,Hong-Xiang Liu,Yi-Xin Lu,Ming-Xin Song,De-Ming Zhao, Xiang-Mei Zhou, Li-Feng Yang, Xiao-Yun Li.Polymorphism of prion protein gene in sheep of Inner Mongolian,China,Virus Genes.2010

45 近期发表的 TSE 相关中文文章 1. 鲁云, 杨利峰, 赵德明羊瘙痒因子 263K 感染中国金黄地鼠后生物学特性的检测, 中国畜牧兽医, 鲁云, 杨利峰, 赵德明朊病毒检测方法概述, 中国畜牧兽医, 王伊琴, 赵德明等热力学因素对绵羊重组朊蛋白体外构象转化的作用中国农业大学学报,2009,14(4): 张交儿, 王志远, 黄瑛, 王洋, 尹晓敏, 周向梅, 赵德明 12TNF-α 在 IFN-γ 诱导的感染牛分枝杆菌的 THP-1 细胞凋亡过程中的作用及相关信号通路分析畜牧兽医学报 ISTIC PKU 年 5 期 5. 许立华, 康晓东, 涂健, 张珠明, 杨建民, 周向梅, 尹晓敏, 杨利峰, 赵德明朊蛋白在宁夏滩羊不同组织中表达的免疫组化研究畜牧兽医学报 ISTIC PKU 年 3 期 6. 乔俊文, 苏晓鸥, 王伊琴, 周向梅, 杨建民, 尹晓敏, 马李颖, 赵德明绵羊组织中朊病毒受体 37kDa/67kDa LRP/LRmRNA 转录水平研究畜牧兽医学报 ISTIC PKU 年 7 期 7. 王伊琴, 秦贞奎, 包勇敢, 寇福军, 荆文奎, 乔俊文, 赵德明内蒙古地方品种绵羊朊蛋白基因多态性分析畜牧兽医学报 ISTIC PKU 年 5 期 8. 白瑜, 周向梅, 尹晓敏, 杨建民, 赵德明 26PrP 诱导的小鼠成神经瘤 N2a 细胞 NF-κB 激活及神经毒性研究 [ 畜牧兽医学报 ISTIC PKU 年 4 期 9. 白瑜, 李玉荣, 周向梅, 尹晓敏, 赵德明 32PrP 诱导的 N2a 细胞神经毒性中神经营养因子受体 p75ntr 的表达变化研究畜牧兽医学报 ISTIC PKU 年 3 期 10. 白瑜, 张交儿, 尹晓敏, 周向梅, 赵德明朊蛋白多肽 PrP 对 N2a 细胞活性及 PrP mrna 表达的影响中国兽医杂志 PKU 年 6 期 11. 张奥, 余琦, 周向梅, 刘爱林, 赵德明绵羊朊蛋白 PrPC 蛋白酶 K 抵抗片段的克隆原核表达及纯化中国兽医杂志 PKU 年 3 期

46 领导关心教育部吴启迪副部长来 NATSE 实验室指导工作吴邦国委员长视察 NATSE 实验室农业部兽医局张弘副局长来实验室指导

47 领导关心

48 学术团队

49 谢谢! THANKS

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