Molecular Pathology introduction ???????

1
Molecular Pathologyintroduction???????

• ??????????
• ? ?

2
Pathology

• What are the specific changes in function and
  structure that characterize each disease?
• Level A. Naked eye level
• gross changes in diseased
  organs.
• Level B. Light microscopic level
• in histological and cytological
  level.
• Level C. Electron-microscopic(EM) level
• in the ultrastructure (cellular
  organelles).
• Level D. Molecular level
• inspect aberrant in DNA, RNA, and
  protein.

3
??? ??

• ?????(molecular pathology)??????????,?
  ??????????????????????????????
• ????????????????
• 1. ?????????????????????,???????500D
• 2. ?????,??????????????????,?????????????????

4

• ???????????????????????????????????????????????
  ???????,??????????????????
• ???????????,????????????,??????????????
  ???????????????,????????????????

5
??? ?????????????

• ??????????
• (?)???
• ???????????????????????????,???????????????
• ????????????????,???????(???)??????????????

6

• (?)????????????
• ?????????????????????????????????(gen
  ome)?????????????
• ?????????DNA,DNA?????????,??,?????????????????????
  ?,?????DNA????,???????????????????
• 2. ??????????DNA,??????????DNA,??????tRNA?rRNA????
  ???????

7

• 3.?????mRNA????????????,???????,???mRNA????,??????
  mRNA?????,?????????????,??????????????,?DNA?????,?
  ??????DNA????????????,?????????????????
• 4. ??????????

8
(??WWW.DXY.cn)
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(??WWW.DXY.cn)
10
?? ??????

• (?)???
• ?????????????????????????,????????????????????,???
  ?????????????????????

11

• ?????????
• 1.???????????????????????????????????????,??????
  ???????????????????????,??????????????????????????
  ,???????,??????

12
????
13
???
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• 2.?????????????????????????,????????,?????????,??
  ???????
• ???????(complex genetic disease)
• ?????????????????
• ???????????,?????????,?????????????????????????
  ???,???????????(majorgene)?
• ????,??????????????????(??),???????????

15

• ??,??????????????,????????
• (1)????????????
• ????????????????????????????????????????????????
• ????????,?????????????????????????????(?????),??
  ?????????????????????????,???????,????????,???????
  ?????????????????????

16

• ????????????????
• ?????
• ??????????
• ?????(???????SNP?)?????,??????????????????????
  ?,????????????????????????

17

• ????????????????
• ???(haplotype)????
• ???(haplotype)?????????????(haplotype
  mapping)????,????????12??????(haplotype
  block),????????25kb,????????????,????????1????????
  ,?????????,????????,???????????????,???????,??????
  ???????

18

• ?????????(Haplotype map, ????HapMap)??????????????
  ?????????
• ??????????????????DNA???????????????,?????????????
  ???????????????

19

• ???????(single nucleotide polymorphism,??SNP)?????
  ?????????????????DNA?????,????1?
• SNPs???????????,??????????????,?????????????,?????
  ?????????(RFLP)???????????????

20

• SNP???????????????????,???????????????????????????
  ????????????????SNP??????
• ?????????????????????????????????????????SNP??????
  ???,?????????????
• ??,?????????????????HapMap??????????????????????
  ???,?????????????,??????????????????????????

21

• HapMap???????????SNP???(block)???
• SNPs?????????????,?DNA????????---???
• ????????????,???????????????DNA??,?SNPs???????????
  ??,????(Haplotype,?1)?
• ?????DNA??????????????SNP????????????

22

• ???,?????????,???????????(tag)SNPs,????????????
  ?
• ?????????????SNPs?????????????,?????????????
• ?????SNP?????????,????????????????????????
• ???????????????????,??????????????SNP????,????
  ??????????SNP?????

23
? ???????a ??DNA??SNP?????4?????????????????DNA???
?????????3???????????SNP??????????(alleles),???SNP
????????C?T?b ??????Haplotypes???????SNP??????,???
????6000 bp DNA???????20?SNPs?????,??a??3???(?????
),?????????????Haplotypes 1-4?c
??SNPs???????20?SNPs??3?,?????????????????,???????
???3???SNPs?A - T C,?????????1?(???The
International HapMap Consortium. The
International HapMap Project, Figure 1. Nature,
2003426)
24

• ?????????SNPs???????,?????????????????????????????
  ,???????????????????
• ??,???????????????????,???????????????????????????
  ??????????????????????????
• ??????????????????????????????????????????????????
  ?????????????

25
(No Transcript)
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(No Transcript)
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(No Transcript)
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(No Transcript)
29
??? HapMap
30

• HapMap??????????????????,?????????????DNA?????????
  ?????????????????
• HapMap???????HapMap????????????????????????,??????
  ??????????????????????????????,???????????????????
  ?

31

• ??????DNA?????????????(A)?????(T)????(C)????(G
  )?????????????23?????????60?????????????
• (?http//www.dnaftb.org/dnaftb/?????????)???????
  ?????????????????????????????????????????

32

• ???????????????????????,???DNA???????????????????
• ??,????1200??????????????(?1)??????????A,?????????
  G??????????????????????DNA???
• ?????????????????????(allele),??????????????????
  ?????

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?1??????????7????????DNA???, ?2200???????????????
??(SNPs)?
34

• ???????????????????????,??????????????????SNPs(???
  snips)?
• ?????????????????????????????????SNPs????,????????
  ????????????

35

• ???????,SNPs??????????????????????????????????????
  ,
• ???????????????????????????????????????SNPs?
• ?????SNP??????????,??????SNP?????????????????????
  

36

• ??,?????????????????SNPs????????
• HapMap??????????????SNPs????????????????????
• ????????????????????????,????????????A???G????,???
  ?????????SNPs????????????????????????

37
?2HapMap?????????(a)??????DNA????????????(SNPs)
(b)????????1??????????SNPs??????(c)?????????????
??????SNPs???????????SNPs??????,??????????????????
?????????
38

• ????????????,???????????? ?????????,55???????????
  ?,30????????????,8????????????,?????????????????
  ??
• HapMap????????????????????????,??????????????SNPs?
  ?????????SNPs(?????????),
• ???????????????????????????????????????SNPs??????3
  0??60?,??????????SNPs?

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• ???HapMap?????SNPs???,?????????????????????????
• ????????????????????,?????????????SNPs???,????????
  ??SNPs??????????????????????
• ???????????????????????,??????????????????????????
  ?????????????????????,????????????????????????????
  ?

40
??????
41

• ????????????????????????????????????
• ?????,?????????????????????????,??????????????????
  ?????????????
• ?????????????,????????,???????????????????????????
  ????????????????,????????

42

• ????,?????????,????????????????????????????
• ??????????????????DNA?????(?1)??????????????,?????
  ????????????
• ?????????,????????????????????????????????

43
?1????????????????????????????????????????????(?X
????)????????????,???????????????X????????????????
?X??????????SNPs???????????
44

• ??????????????15??????,????????????????????????
• ??????????????,?????????????????????????????
• ??????????,????????????????????????,??????????????
  ????????
• ?????????????????????,???????????,???????????????

45

• ????????????,??????????????????,????????????????
• ??????????????????????,????????????????????????DNA
  ??????
• ??,DNA??????(???),??????????,?????????????????????
  ???????????

46
??????????
47

• ??HapMap??????????????????????????????????????????
  ???????,??????????????
• ????????DNA???????????,??????????????????????????
  ??????????????????????????????????,?????????????
• ????????????????????????????,??????????DNA????????
  ???,??????????(phenotype)????????????

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• ???????????????,???????????????????
• ??,???????????????????HapMap???????????????????
  ,??HapMap?????????????????
• ??,???????????????????????????????????????????,???
  ??????????????????????????????,???????????????????
  ????,???????????????

49

• ??,?????????????????????????????????
• ???????????????????????????,???????????HapMap?????
  ?????
• ??,??????????????????????????????????

50

• ??,?????????????????????????????????????????????
  ?
• ???,?????????????????????????????????????,????????
  ??????????????

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• ????????????????????DNA?????????????????,????
  ????? ,??????DNA?????HapMap???????????????????????
  ????????????,?????????????????????????

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• ??,????????????????????,HapMap???????????
• ????????????,??????????????????????????,?????????,
  ?????,???????????????????????????,????????????????
  ?????????????????
• ?????????????????????????????,????????????,???????
  ???????HapMap?????????
• ??,????????????,?????????????????????

53

• ???????????,???????(CAG)???????????Coriell??????,?
  ?????????????????????
• ???????????????,??????????????????????????????
• ????,????????????????????,????????????????????????
  ????????????????

54

• HapMap????????????????
• ??,????????HapMap?????????????,???????????????????
  ?
• ???????????,HapMap????????????????HapMap??????????
  ?

55
?????
56

• ?????????????????????????????????/?????????????(ht
  tp//www.genome.gov/10001685)??????????????,??????
  ???????
• ?????????????????????????????,????????????????????
  ?
• ??????????????????????,???????????????????????????
  ?????????????CEPH????????????????,????????????????
  ??????,???????????????????????????

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• (2)????????????????????DNA?????????
• ??????????????
• ? ??? ???????????????
• ?????(epigenetics) ????????????????,??????????????
  ??????????

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• (2)????????????????????DNA?????????
• ???????DNA?????,?????????????????????????
• ??????,?????(? )?????(???)?????????(????????????)?
  ????????????
• ????????????????????,????????????,??????????
• ?????????????????,?DNA???????????????????????????

59

• ??????????????????????????????????????????????????
  ?????????CpG????????????.
• (????????????,?????????????????????????,??????????
  ???????,???????????????????(genomicimprinting)?
• ???(?)?????????,????(?)???????????????????,???????
  ??????????????????????????????????????)?

60

• 3.??????
• ????????,??????,??????????????

61

• (?)???
• ???????????,????????????????,???????????????,?????
  ???????????????????????????????????????

62

• (?)???
• ???????????????,??DNA????????????
• ??DNA????????????????,????????????????????????????
  ????,?????????
• ??????????????????,?????????????????????????????
  ???????,????????(ß?????????????HbS)?

63
??? ????????

• ??????????
• ????????????????
• ???????16569bp??????????,????????????
• ????D-??,??D??????16024576 np,?????1122bp
  ?????????
• ??????16024-16383np,
• ??????57-372np,
• ??????438-574np?

64
??? ????????

• ??????????
• ??mtDNA??????????????,???????????
• ??????????????????,???????????????????????????????
  ?????????
• ?????????????????????????????????????????,????????
  ???
• ?????2?rRNA ???22?tRNA???13???????(??????????????,
  NADH ????7 ???,????b ??ATP ?6 ?8 ??)?

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• (?)??????
• 1. ????????????????????
• 2. ???????????????????????mtDNA??! ?????????????
• 3. ???? ??mtDNA??,?????DNA ?10?
• 4.???????????????mtDNA????????????????,??????????
  ??????
• 5. ??????mtDNA???????,?????????
• 6. ????

66

• 7. ??mtDNA?????????,?????????????
• 8. ????????????????????????????
• 9. ????????????????????
• 10.?????????DNA?RNA??????????????????,???????????
  ??????DNA?mtDNA???,??mtDNA ???????????????????????
  ?????????????????mtDNA????????????????????

67
?22-2 ??????????(??Medical Genetics,???????)
68

• (?)?????????????????
• ???????????mtDNA????DNA???????????
• ?????mtDNA???????????????,???????????????mtDNA????
  ????,??1mg??????0.2-0.5ug mtDNA.???????mtDNA??????
  ??

69

• ???DNA??????mtDNA??,?????????
• (1)?????????(??????????????)???????(???????tRNA??
  ??,??????)?
• (2)??-????????mtDNA????????,????????????

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• ???DNA??????mtDNA??,?????????
• mtDNA?????????, ????D310????D??303-315np ?polyC
  ??,?????????,?????????????????????????????????????
  ????D310???????????????????mtDNA ?????????
• ???????mtDNA???????DNA??????,???????????DNA??????
  ????mtDNA????????????,???mtDNA?????,??????????????
  ???

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• ???????????
• (?) ???????????
• ????(cytoskeleton)???????????????????????????,????
  ???(microtubule)???(microfilament)????(intermediat
  e filament)??,???????????????

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• 1. ?? ???????????,???22nm,???15nm.????13????(prot
  ofilament)??????,????????(tubulin)???????????????
  ??,?????????????????????????????,???????????????
  ????????????????????????????????????????

73
????????(??www.DXY.cn)
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• 2.??? ?????7-11nm,????????????,????????????,?????
  ?????????,???????????????????????????,????????????
  .
• 3.?? ?????6nm,?????(actin)???????????.?????????43
  kD,???????????(domain)??,???????????(ATP?ADP)?????
  ?(Ca2?Mg2?Sr2)??????

75
?????????? (??www.DXY.cn)
76
??????????????(??www.DXY.cn)
77

• (?)?????????
• 1. ???????
• ???????????????????,?????????????????????????????.
  
• (1)???????? ??????????,??????????????????????????
  ??,????????????????,???????????
• (2)?????? ????????????????????????.??????????????
  ?????????????????????????????????,?????,?????????
  ????
• (3)????????? ???????????????????????????????????,
  ????????????

78

• 2. ???????
• ??????????????????????????????????????????????????
  ??????????????????????????

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• 3. ???????????
• ?????(Alzheimer disease,AD)????????????????????,??
  ????????????,?????????tau??,??????????????????????
  ????????????????tau???

80
4. ???????????????
?-1 ?????????????
?? ???? ?? ????
EBS ????? ????? x5,k14
EBS?????? ????? ?? plectin
EBS?????????? ??????????? ?? bpag1
EHK?EPPK ????? ????? k1?k10?k2e?k9
?????? ???? ?? k6?k16?k17
????? ??????? ?? k4?k13
???? ?? ?? ???? hb6
??????????? ? ????? k18
?????? ?? ?? k8
??????? ????? ?? nf-1
???????????????(???????)???????2002 EBS
???????????( epidermolysis bullosa simplex,
EBS) EHK??????????(epidermolytic hyperkeratosis,
EHK) EPPK???????????(epidermolytic palmoplantar
keratoderma, EPPK)
81
??? ??????????

• ?? ?????
• ???(biological membrane),???????????????,?????????
  ??????????????,???????????????,???????????????????
  ????,????810nm??????????????????????????,????????
  ???????
• ???????????????????????

82
??????????

• ?????????????????,????(plasma membrane)???????????
  ????????????????????????????????,????????????????
  ??????????????,????????????,?????????????????????
  ??????,?????????????????

83
?22-3 ??????????(??basic histology,?????)
84
?????????

• ??????
• ???????????????????????????,??????????,??????????
  ???,????????????????,???????

85
?????????

• (1) ??????
• ????????????????????,??????????????????,?????????
  ???????????,?????????,?????????????????????????
• ??????????????,????????????,?????????????,?????
  ??????????????????????????????,?????????????

86

• ??????????????????????????????,?????????????
• ?????????????????????????????,?????????????????,?
  ?????????????????
• ?????????????????????????????????????????(CEA),??
  ?????????????????ß????????????????(EGF)????????50?
  ??,??????????????????

87

• ???????????????????,????????,?????????,??????????
  ???????,?????,??????,???????????
• ????????????????????????????????????,??????????,?
  ???????????,????????,???????

88

• (2) ?????????
• ?????????????????????????????B??????,????????????
  ??????????????????LDL????????LDL?????????????????
  ?
• ????????????????????????????,??????????????????

89

• (3) ?????????
• ???????????????????????????????
• ?????????????????????????,???????,??????????,????
  ?????,????????????????????
• ??????-????????????????,????????????????????????-
  ??????????,??????????

90
??? ????????????

• ?????(extracellular matrix,ECM)???????????????????
  ??????????????
• ??????????????

91
????????????

• ?????????????????????????,??4060nm.???,?????????3
  ???(??????)???????(??????)?

92
????????????

• ??????,?????????????,???????????(laminin)?????(pro
  teoglycan)????(nidogen)????????????????,?????????
  ??(fibronectin)??????(chondroitin sulfate)?
• .
• ??????????????????????,?????????????????????????
  ????,?????????????????

93
??????????

• ??????????????????????,??????????????,???????????,
  ????????????????????????????????????????????????
  ????????

94

• ???????????????
• ??????????????????,????C????????????????????????
  ?????????????
• ??????????????????????????????????,???????????????
  ????????????????,????????????????

95

• 2. ????(fibronectin)??
• ??????????DNA???????????????????????????,?????????
  ???????,??????????????,???????????

96

• 3.????(laminin)??
• (1)?????????????????????????????????????????
• (2)??????????????????????????????????,?????????,?
  ??????????,?????????????????????????????

97

• 4.????(proteoglycan)??
• ?????????(??????)??????(coreprotein)???????
• ?????????????????????????????,????????????????????
  ??
• ????????????????????????,???????????,??????????,??
  ?????,????????????????

98
(??WWW.DXY.cn)
99
(??WWW.DXY.cn)
100
??????

• 1. ?????????? ???????2002
• 2. ???. ??????? ???? ????.20041(8) 61
• 3. The International HapMap Consortium. The
  International HapMap Project. Nature, 2003426
• 4. ??????????????????????????????,200325(6)24
• 5.???,???,???. ??????????????????????????
  .??????????? 20032(4)260
• 6.El-Osta A. The rise and fall of genomic
  methylation in cancer. Leukemia ,2004 , 18 (2)
  233237.
• 7.???,?????????????????? ????????200425(2)117
• 8. George H.Sack,JR. Medical Genetics.
  McGRAW-HILL Companies,1999.
• 9.???,???,??????????????????????????,?35??3?,2004?
  6??
• 10.Luiz Carlos Junqueira,Jose Carneiro. basic
  histology Text Atlas,10th edition.Lange Medical
  Books McGraw-Hill,2003

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