2022 Fiscal Year Research-status Report
Functional and pharmacological investigation on novel KCND3 variants identified in patients with early repolarization syndrome and refractory epilepsy
Project/Area Number |
22K20906
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Research Institution | National Cardiovascular Center Research Institute |
Principal Investigator |
ビャムバジャブ ツェレンハム 国立研究開発法人国立循環器病研究センター, 研究所, リサーチフェロー (60963527)
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Project Period (FY) |
2022-08-31 – 2024-03-31
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Keywords | KCND3 / potassium channel / early repolarization / epilepsy / Kv4.3 / patch-clamp method / sudden cardiac death |
Outline of Annual Research Achievements |
The aim of this study is to elucidate the electrophysiological changes of novel KCND3 variants and to analyze the pharmacological effect of drugs to the variants. The variants are the cause of refractory epilepsy and might be related with early repolarization syndrome leading to sudden cardiac death in epilepsy (SUDEP). We have successfully created a cultured cell model with transiently expressing KCND3 encoding Kv4.3. The variant Ito channels caused gain-of-function effect: increase of Ito densities, leftward movement of activation and inactivation curves and slow inactivation. In addition, the variant showed slow recovery from inactivation. Therefore, we have applied some candidate drugs to variant channels and identified their promising effects.
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Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
The study is progressing according to the plan. Results have been and planned to be disseminated in academic conferences (JCS2023 in March and Heart Rhythm Society Annual Meeting in May).
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Strategy for Future Research Activity |
We have planned to apply several candidate drugs to the variant channels and some of the drugs would be applied.
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Causes of Carryover |
This fiscal year, manual patch-clamp method has been performed to screen candidate drugs in wild and variant Ito channels, and next fiscal year we are planning to perform automated patch-clamp system (Patchliner by Nanion technologies) which would allow us to evaluate more candidate drugs in shorter time. Therefore, some preparations have been carried out including the development of a stable cell line and training to work in the new system. Some findings were presented at the domestic conference, and in the next fiscal year, we will disseminate the results at the international conference.
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Research Products
(2 results)