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王世鑫 武警医学院科研部 武警医学院蛋白质组学实验室 PowerPoint PPT Presentation


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医学科研思维方法. 王世鑫 武警医学院科研部 武警医学院蛋白质组学实验室. 一、白色、黑色和灰色系统与医学研究 (一)客观世界划分为白色、黑色和灰色系统 系统论、信息论和控制论自从上世纪诞生以来,很快成为人们认识复杂客观世界新的哲学思想和方法体系。白色、黑色和灰色系统三个系统的划分,为科学研究从总体思维上廓清了大环境,为探索繁杂艰难的医学问题提出了一个可共选择的思维格局,便于根据问题的系统性状,来选择合理有效的研究技术和方法。从宏观上为医学科学研究建立了一个科学思维的框架。. 第一节 医学科研的思维方法.

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王世鑫 武警医学院科研部 武警医学院蛋白质组学实验室

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CT

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mRNA


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200221

2003


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Leroy Hood


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Institute for Systems Biology

founded byLeroy Hood in 1999


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DNA


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/


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VEGF protein is secreted outside the cells and binds to its receptor on the endothelial cells to promote their growth.


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(D)(S)

P

D

S

P1

E

Pe

P2

D

S

P

P

O

Q4

Q2

Qe

Q1

Q3

Q

P1Q1Q2OQ1>OQ2

P2Q3Q4OQ3>OQ4


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(1)EE

(2)

(3)

(4)


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  • Dulbecco 19861990


Many genome

The public project estimates that there are 31000 protein-encoding gene, whereas Celera finds 26000, with many more still to be found.

6000 for a yeast

13000 for a fly

18000 for a worm

26000 for a plant

(Genomes Online Database)

Many Genome


Proteome

The total PROTEin composition of a genOME.

M. Wilkins et al. Electrophoresis 1995, 16, 1090-1094

Proteome describes the complete set of proteins that is expressed, and modified following expression, by the entire genome in the lifetime of a cell.

It describes the composition of proteins expressed by a cell at any one time.

Proteomes are dynamic!!!!!!

Proteome


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Duodenum smooth muscle

Ileum adipose

Thyroid gland

Brain medulla oblongata

Placenta whole

Brain putamen

Oesphagus smooth muscle

Stomach fundus smooth muscle

Ileum smooth muscle

Oesphagus mucosa

Kidney pelvis

Lung whole

Liver anterior right lobe

Bladder fundus outer wall

Blood vessel pulmonary artery

Colon mucosa

Colon taeni coli

Pancreas whole

Uterus myometrium (myometrial)

Jejunum mucosa

Blood vessel cerebral artery

Stomach antrum smooth muscle

Lung 2 bronchus

Foreskin

Lung trachae whole

Brain frontal cortex

Stomach fundus mucosa

Lung parenchyma

Stomach body mucosa

Brain cerebellum

Heart pericardium

Pituitary gland whole

Ceacum mucosa

Ileum mucosa

Spleen whole

Brain amygdala

Gall bladder whole

Cell line 132N1

Brain hypothalamus

Tonsil (lymph node)

Brain caudate

Ceacum smooth muscle

Aorta whole

Umbilical cord whole

Bladder trigone

Stomach body smooth muscle

Testes whole

Lung 4 bronchus

Colon smooth muscle

Kidney renal cortex

Brain superior frontal gyrus

Brain caudate putamen

Brain striatum

Cell line HeK293

Lung 1 bronchus

Brain substantia nigria

Kidney renal medulla

Lung 3 bronchus

Skeletal muscle

Blood vessel basal artery

Brain choroid plexus

Brain hippocampus

Kidney ureter

Duodenum mucosa

Protein Expression

mRNA Expression

5

4

3

2

1

0


Differential expression at differential temperature

Differential Expression at Differential temperature

A

B

E. Coli grown at 30 C

E. Coli grown at 42 C


Proteomics

Proteomics is the study of protein properties on a large scale to obtain a global, integrated view of disease processes, cellular processes and networks at the protein level.

Cytoplasmic proteins

Proteomics


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B

kDa

A

P07155

P07155

25

Y43753

Y43753

5.5

5.5

pI


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Genomics and Proteomics

Structural Genomics

DNA

Functional Genomics

RNA

Structural Proteomics

PROTEIN

Functional Proteomics

PROTEIN

Protein Chips

Yeast 2-Hybrid

Transgenics

3-D Structure

Bioinformatics

Sequencing

Mapping

DNA Arrays

Bioinformatics

2-D Gels

Mass Spec

Protein Chips

Bioinfomatics

Gene Expression

DNA Arrays

Transgenesis


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VEGF protein is secreted outside the cells and binds to its receptor on the endothelial cells to promote their growth.


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342


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()

()


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()()(

)


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(0) (0+) (I)

C4

-2

-1

-1

3 0+

()


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Healthy

Diseased


Clinical proteomics

1.

(biomarker)

2.

3.

4.

(clinical proteomics)


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()

Products

2-D

/

cDNA//

/

A

B

C

Nano-HPLC

cICAT(Duplex Samples)iTRAQ(Multiplex Samples)

(BioMarker)

2

Biomarkers

4800

MADI-TOF-TOF

PROTEIN ID

/

Bioinformatics

(PMF)

(MSMS)


Seldi tof ms

()SELDI-TOF/MS


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:

()

()

()

()

()

:

(PS-1 or PS-2)

( )

(- )

(DNA )


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Wash Conditions

Measured m/z

pH

Salt

Urea

Water

CHAPS

Organic

Imidazol

60

Detergent

5807.5

40

20

0

2500

5000

7500

10000

Surface Type


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()


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1.

2.

3.


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()

MS


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MALDI TOF/TOF

ESI MS/MS

Western Blotting

Real time PCR


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()


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100xMAP

12L

(SAT)


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xMAP


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xMAP


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  • fluorescent tag


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DATA!

DATA!

DATA!

DATA!

Ex1

Em1

Ex2

Em3

Em2

  • Read 100 each color

  • bead in assay

  • 1 - 100 bead sets avail.

DD


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1.95 ~32000pg0.2~3200pg

35min/96

20s100


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Cytokines

IL-1

IL-1

IL-1ra

IL-2

IL-2R

IL-3

IL-4

IL-5

IL-6

IL-7

IL-8

IL-9

IL-10

IL-12(p40)

IL-12(p70)

IL-13

IL-15

IL-16

IL-17

IL-18

Basic FGF

Cytokines

Human(50

G-CSF

GM-CSF

GRO-

HGF

ICAM-1

IFN- 2

IFN-

IP-10

LIF

MCP-1(MCAF)

MCP-3

M-CSF

MIF

MIG

MIP-1

MIP-1

NGF

PDGF-BB

CTACK

Eotaxin

RANTES

SCF

SCGF-

SDF-1

TNF-

TNF-

TRAIL

VCAM-1

VEGF


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IL-1 Basic FCF TNF-

IL-1 Eotaxin VEGF

IL-2 G-CSF

IL-3 GM-CSF

IL-4 IFN-

IL-5 KC

IL-6 LIF

IL-9 MCP-1(MCAF)

IL-10 M-CSF

IL-12(p40) MIG

IL-12(p70) MIP-1

IL-13 MIP-1

IL-15 MIP-2

IL-17 PDGF-BB

IL-18 RANTES

32


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IL-1

IL-1

IL-2

IL-4

IL-6

IL-10

GM-CSF

IFN-

TNF-

9


Biomarker

Biomarker


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TM9

AFP&CEA2

TM4

TM5

TM5

PSA2


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Akt(Ser473) JNK (Thr183/Tyr185)

ATF-2(Thr71) MEK1 (Ser271/Ser221)

c-Jun(Ser63) NK-Bp65(Ser536 )

CREB (Ser133) p38 MAPK(Thr180/Tyr182)

EGFR(Tyr) p53 (Ser15)

ERK1(Thr202/Tyr204) p70 S6 kinase(Thr421/ Ser424)

ERK2(Thr185/Tyr187) p90 RSK(Thr359/ Ser363)

ERK1/2(Thr202/Tyr204, Thr185/Tyr187) PDGF receptor-(Tyr751)

GSK-3/(Ser21/Ser9) S6 ribosomal protein (Ser235/Ser236)

Histone H3(Ser10) STAT2 (Tyr689)

HSP27 (Ser78) STAT3 (Tyr705)

IB- (Ser32/Ser36) STAT6 (Tyr641)

IRS-1 (Ser636/Ser639) TrkA (Tyr496)


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Akt(Ser473) HSP27 (Ser78)

ATF-2(Thr71) IB- (Ser32/Ser36)

c-Jun(Ser63) JNK (Thr183/Tyr185)

CREB (Ser133) MEK1 (Ser271/Ser221)

ERK2(Thr185/Tyr187) p38 MAPK(Thr180/Tyr182)

ERK1/2(Thr202/Tyr204, Thr185/Tyr187) p90 RSK(Thr359/ Ser363)


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IL-8

IL-6

4.752.54pg/mL

IL-10

0.290.07 pg/mL


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(ProteomeWorks System)

Consumable Supply

Part II

2D Electrophoresis

Part III

Imaging Analysis

Public Instruments

ChemiDoc XRS

Part I

Sample Preparation

Public Instruments

Prep 491

(

Part IV

Spot Cutter&Mass

Public Instrument

EXQuest Spot Cutter

with Fluorescent

Mass Import

Bio-Plex

IEF(

+Mini P 3

+PROTEAN II XL

(2

+ PROTEAN II

Dodeca Cell

(12

DodecaStainer

PDQuest

Worksbase Bioinformatics Workstation


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Ph. D. 308120,SCI8

:1

2

1

2

3

3

4

5

6

7


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200730771788, 32

2006 20

2006 20

200626

SARS 2005 30

SARS, 200312

2003 20

2001 16


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[1] Lianteng Zhi, Gangqiao Zhou, Hongxing Zhang, Yun Zhai, Hao Yang, Fang Zhang, Shixin Wang,Maoti Wei, Wuchun Cao &Fuchu HeLack of support for an association between CLEC4M homozygosity and protection against SARS coronavirus infectionNATURE GENETICS2007,39(6):692-694( SCI,IF24.59)

[2] Shi-Xin WANG, Xue-Feng ZHAO, Jia-Wei Zeng, et al.Screening of serum biomarkers and establishment of decision-tree in silica-exposed populations by SELDI-TOF-MS [J]JOEM. 2007,49(7):764-770 (SCI,IF1.88)

[3] WANG Shixin, LIU Ping, Wei Maoti, et al.The roles of serum CC16 and SP-D on early diagnosis and progression of silicosis [J]JOEM. 2007,49(8):834-839 (SCI,IF1.88)

[4] Sh.X. Wang, Y.M. LI, B.C. Sun, S.W.Zhang, W.H.Zhao, M.T.Wei, K.X,Chen, X.L.Zhao, Z.L.Zhang, M.K.,A.C.Cheung, and P.P.Wang. The SARS outbreak in a general hospital in Tianjin, China-the case of super spreader. Epidemiology and Infection. 2006,134:786-791www.outbreak-database.com(SCI,IF1.79)

[5] PEI Li-ying, GAO Zhan-cheng, YANG Zhen, WEI Dong-guang, WANG Shi-xin, JI Jian-min, JIANG Bao-guo. Investigation of the influencing factors on severe acute respiratory syndrome among health care workers. Journal of peking university(health sciences). 2006,38(3):271-275

[6] WangShiXin,Weimaoti,Yangzhen, et al. A seroepidemiological study on SARS after the outbreak in a hospital .International Workshop on Epidemiological Studies of the SARS Outbreak in China


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[7] WANG Shixin,DU Haike,ZHANG Xizheng,CAI Shaoxi,FAN Huaquan,WANG Chang'en. Effects of niacin on nitric oxide synthase expression in rat lungs exposed to silica. PROGRESS IN NATURAL SCIENCE,2004,14 (12):1069-1073(SCI,IF0.58)

[8] Zhen Yang, Peizhong Peter Wang, Maoti Wei, Shixin Wang, Zhanliang Cao1 , Yuming Li, Zhenshan Jiao, Shulin Yuan and ZhilunZhang. A longitudinal sero-epidemiological study in recovered SARS patients and controls after an outbreak in a general hospital, Clinical and Vaccine Immunology2007 submitted

[9] Maoti wei yi han li he keju zhang zhen yang bin su zhilun zhangshixin wang. Roles of TGF-1 polymorphism in the occurrence and progress of SARS-Cov infectionEurope Journal of Epidemiology2007 submitted

[10] Wang Shixin, Wei Maoti, Li Yuming, Chang Aihua, Gao Xiuxia, , LiuYan,Yang ZhenThe Emergence and Containment of Severe acute respiratory syndrome epidemic in a general hospitalInternational Journal of Public Health and Tropical Medicine2007 submitted

[11] Shixin Wang, Maoti Wei, Zhen Yang, Yi Han, Li He, Keju Zhang, Bing Su, Hongsheng Gao, Yilan Hu, Wuli Hui, Zhilun Zhang The influence of TNF- gene polymorphism to the occurrence and progress of SARS-Cov infection, BMC Infectious Disease2007 submitted

[12]2-DEMALDI-TOF MS/MS [J]2007 ,25(3),56-61


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