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 Category |
Grant-in-Aid for Research Activity Start-up
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Allocation Type | Multi-year Fund |
Review Section |
0902:General internal medicine and related fields
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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, オープンイノベーションセンター, 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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Project Status |
Completed (Fiscal Year 2023)
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Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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Keywords | potassium channel / Kv4.3 variants / electrophysiology / gain-of-function / neurological disorders / KCND3 / early repolarization / epilepsy / Kv4.3 / patch-clamp method / sudden cardiac death / arrhythmia / SSRIs / refractory epilepsy |
Outline of Research at the Start |
KCND3 variants were identified in patients, and the pathogenicity of these variants have not been elucidated. We have already constructed the plasmid with these KCND3 variants. Using cultured cells transfected with KCND3 variants, I try to elucidate the electrophysiological mechanism of early repolarization (RE) by patch-clamp method, and the analysis will be beneficial for the elucidation of the pathogenesis of SUDEP. Next, I search for effective therapeutic agents for pediatric patients with RE.
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Outline of Annual Research Achievements |
Sudden Unexpected Death in Epilepsy (SUDEP) is one of the most frequent causes of death in patients with refractory epilepsy (RE). We identified two novel KCND3 variants in young patients with RE though the functional properties of these variants have not been elucidated. We aimed to elucidate the electrophysiological changes of novel KCND3 variants and to analyze the pharmacological effect to the variants. 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, slow inactivation and slow recovery from inactivation. We investigated promising effects of candidate medicines.
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Report
(2 results)
Research Products
(5 results)