Tomaselli Lab Department of Medicine Division of Cardiology Ross 844 [email protected] GFP-LC3 Cx43...
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Transcript of Tomaselli Lab Department of Medicine Division of Cardiology Ross 844 [email protected] GFP-LC3 Cx43...
Tomaselli Lab
Department of MedicineDivision of Cardiology
Ross [email protected]
Cx43
MERGE
5 mm
WT IQ/AA
1 sec
0
WT
IQ/AA
IQ/AA + Ranol
Areas of Research Interest• Cardiac Ion Channel structure-function and
regulation– Na, K channels– Connexins
• Cellular and Molecular Remodeling in the Diseased Heart– Heart failure and CRT
• Mechanisms of Sudden Cardiac Death– PROSE-ICD
Na channel regulation Channel mutation in a patient
WT R526HS528A
NaV1.5 I-II linker
PKA:substrate = 1:50
PKA:substrate = 1:1
Total protein
WT R526H S528A
dsRED-ERNav1.5
A
CaMKII0
10 pA/pF
5 ms
CaMKII +AIP0
Control0
B
Membrane potential (mV)
Control
AIP
CaMKII
CaM
CaMKII +AIP
CaM +AIP
0
0.2
0.4
0.6
0.8
1
-120 -100 -80 -60 -40 -20
I /Im
ax
-12050 ms-140
-20 -20500 ms
C
0
1
2
3
4
56
7
8
9
10
-60 -50 -40 -30 -20 -10 0 10
mV
tau
fast
(m
s)
*
* *
Membrane Potential
*
I Na N
orm
(%
)
20 %
100 msCaMKII
ControlD
E
late
I Na (
% o
f pea
k) 0.2
0.4
0.6
0.8
1
1.2
Control CaMKII CaMCaMKII+AIP PKA
*
Ca/CaM/CamKII regulation of Na channels
Mouse model – defective CaM regulation5 mm
WT IQ/AA#724 (281d) #715 (281d)
A
WT IQ/AA
B
Age (months)
20
30
40
50
60
70
0 3 6 9 12
WT
IQ/AA
FS
(%
)
**
Age (months)
HW
/TL
(m
g/c
m)
60
80
100
120
140
0 3 6 9 12
WT
IQ/AA
*
*
100 ms
WT
IQ/AA
WT IQ/AA
RR (ms) 146 140
PR (ms) 38 39
QRS (ms) 13 13
QT (ms) 38 55*
QTc (ms) 103 144*
1 sec
0 WTIQ/AA
IQ/AA + Ranolazine
Remodeling of the diseased heart
HF – Ca handling and adrenergic signaling
HF-synch
*†
CaT amplitude (Lateral)
F405
/485
Cont DHF CRT
*
**
0.2
0.4
0.6
0.8
1.0
0
baselineISOFSK
1.0
NF DHF CRT HF-sync
500 msbaseline
ISO
Transcription Profiling in HF and CRTDHF NF + CRT
NF DHF CRT
A B
C
EF (%
)
0
10
20
30
40
50
60
70
NF DHF3wk 6wk
CRT3wk 6wk
p<0.04
PROSE-ICD Candidate Gene SNPs
0 50,000,000 100,000,000 150,000,000 200,000,000 250,000,0000
0.5
1
1.5
2
2.5
3
3.5
4
rs10774048, CACNA1C
rs2167385, GPD1L
rs9897584, KCNJ2
rs6673954 RYR2rs6700557
p = 0.05
p = 0.01
- lo
g1
0(P
val
ue)
Genomic position