bb - 新技術説明会bkb6 3 %m" b+beb. &"n + b1b-b 5 " b*b bnaï1® µ 6...
TRANSCRIPT
1
TRPV2
2
3
TRPV2
4
5
X linkedrecessive
Autosomalrecessive
Autosomaldominant
DMD dystrophin Xp21.2
fukutin 9q31-q33laminin -2 chain 6q2
12q13
LGMD1A
integrin -7collagenVI 21q22.3
LGMD1BLGMD1CLGMD1D
myotilinlamin A/C
5q311q11-21
caveolin-3 3p257q
LGMD2A calpain-3 15q15.1-q21.1LGMD2BLGMD2CLGMD2DLGMD2ELGMD2FLGMD2G
dysferlin-sarcoglycan
2p1313q12
sarcoglycan 17q12-q21.33sarcoglycan 4q12sarcoglycan
LGMD2H
5q33-q34telethonin
9q31-q34.117q12
4q35
19q13.2-q13.3
FCMDLAMA2ITGA7COL6A2
DMD dystrophin Xp21.2
EMN emerin Xp28
putative E3ubiquitin ligase
LGMD2I FKRP fukutin relatedprotein
19q13.3
TRIM32TCAPSGCDSGCBSGCASGCGDYSFCAPN3
MYOTLMNACAV3
DMPK myotonica protein kinase-sarcoglycan 7q21SGCE
gene gene product locusdiseaseinheritance
mdx
1/3300
6
TRP
VR1(TRPV1)VRL-1 GRC (TRPV2)OTRPC (TRPV4)
CaT2,ECaC1 (TRPV5)CaT1, ECaC2 (TRPV6)OSM9Nomp C
TRPV
TRPN
TRPC
TRPM
TRPML
TRPP
mucolipin
PKD2
TRPC1-7
TRPM1-8
CUP-5
ARD
N C
in
out
ARDARD
TRPV3
TRPV2
[Ca2+ ]i
7
mdxJ2N-k
wild typewild typehamster mouse
Control
Patient 3Patient 2
Patient 1human
TRPV2TRPV2
•
•TRPV2
8
9
NC
NC
LELFKFTIGMGELAFQ LELFKFTIGMGKLAFQTRPV2
[Ca2+]iCK
mdx mdx/Tg
10
00
0.1
0.2
0.4
0.3
0.5
100 200 300 400
0.6
500 600Time(ms)
Forc
e(N
)
00
0.1
0.2
0.4
0.3
0.5
100 200 300 400
0.6
500 600
Forc
e(N
)
Time(ms)
mdx mdx/Tg
0
20
40
60
80
100
1 2 3 4 5 6 7Number of eccentric contraction
Max
imal
forc
e(%
of t
he fi
rst t
etan
us)
mdx
mdx/Tg
WT,Tgmdx mdx/Tg
WT Tg
FEBS Letters 5833600-3604 2009
DN-TRPV2 TRPV2 mdx
11
TRPV2
2
3
4
R34
0/38
0
cont
rol
none
carip
orid
e(1
2, 1
20, 3
60
M)
A(3
, 30,
100
M
)
nife
dipi
ne(0
.06,
0.6
, 2
M)
B(3
, 30,
100
M
)
Polo
xam
er-1
88(3
, 30,
100
M
)
dilti
azem
(3, 3
0, 1
00
M)
stre
ptoo
myc
in(4
0, 1
25
M)
rute
nium
red
(40
M)
Drug ADrug B
100%
2006-0883237
6
5
1
0
12
norm
alno
ne a47
a65
AA
conc a3 a4
8a6
3b6 L0
20
40
60
80
Frac
tiona
l sho
rtni
ng (%
) J2N-kN
norm
alno
ne a65
b33 A a3 a48
a63
b6 L
0123456789
cTN
-I in
ser
um (n
g/m
l) J2N-kN
0
5
10
15
20
none A48 B6 A3
%Fi
bros
is/m
m2
3mm
J2N-k treated with AJ2N-k
J2N-k non treated
13
NC
TRPV2 1
2.
Ca2+ LL
1.
14
•TRPV2
• TRPV2TRPV2
TRPV2
TRPV2
15
• TRPV2
•
• TRPV2
16
•
•
17
• TRPV2
• TRPV2
• TRPV2
• TRPV2
18
• TRP
•
19
• TRPV2
• -• TLO
•
20