| 研究課題/領域番号 |
17K15566
|
|---|
| 研究機関 | 福岡大学 |
|---|
研究代表者 |
フ ヤオペン 福岡大学, 医学部, 助教 (40708476)
|
|---|
| 研究期間 (年度) |
2017-04-01 – 2020-03-31
|
| キーワード | TRPM4 / CaMKII / Arrhythmogenicity |
|---|
| 研究実績の概要 |
(1)In order to get quantitative evaluation on how CaMKII-dependent TRPM4 modulation contributes to arrhythmogenicity, experiments on both expressed HEK293 cells and HL-1 cells were performed, average relationships of steady state open probability and time constant of voltage-dependent activation vs. membrane potential (Vm) at different [Ca2+]i were then reconstructed for both with and without treatment of CaMKII inhibitor KN-62 by using the mathematical expression obtained from experimental data. Gating data indicated that transition sate of TRPM4 channel from the open to closed state was accelerated by CaMKII inhibition.
(2)In TRPM4 expressed HL-1 cells, the incidence of early afterdepolarizations (EADs) was increased after incubation of AngII which induced activation of CaMKII signaling. This arrhythmic change in HL-1 cells could be suppressed by TRPM4 channel blocker 9-phenanthrol and CaMKII inhibitor KN-62.
(3)We incorporated the different rate constants of TRPM4 channel before and after treatment of KN-62 into cardiac action potential (AP) model. Prominent increase in TRPM4 current density induced EADs superimposed on the late repolarization phase. Intriguingly, incorporation of altered rate constant after treatment of KN-62 could alleviate these abnormal activities significantly.
|
| 現在までの達成度 (区分) |
現在までの達成度 (区分)
3: やや遅れている
理由
Experimental results strongly suggested that the mathematical expressions described could be instrumental for predicting the electrophysiological changes induced in remodeled cardiomyocytes with excessive CaMKII activation in silico. However, the difficulties on further validation of present data by animal experiments were beyond expectation.
|
| 今後の研究の推進方策 |
We are going to focus on animal model assessment of CaMKII-mediated TRPM4 regulation.Electrophysiological investigation along with histological and biochemical data, will be used to examine the temporal relationships among cardiac remodeling, arrhythmias and TRPM4 expression/activities in association with CaMKII-mediated signaling. These results will help us to construct the 2D even 3D- cardiac model with reasonable predictability for arrhythmia.
|
| 次年度使用額が生じた理由 |
Research costs will be spent on animal feeding as well as consumables for cell culture, molecular biological, biochemical and electrophysiological experiments. To present the outcome of our study, we plan to attend several conferences and submit experimental results to certain academic journals.
|
