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  11. ストレス活性化キナーゼ ミトゲン活性化キナーゼ-7 動脈動乱の予防のための心臓再偏極化の表遺伝学
  1. ホーム
  3. 研究分野
  5. 生物医学と臨床科学
  7. 腫瘍学とがん発生
  9. 分子標的
  11. ストレス活性化キナーゼ ミトゲン活性化キナーゼ-7 動脈動乱の予防のための心臓再偏極化の表遺伝学

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ストレス活性化キナーゼ ミトゲン活性化キナーゼ-7 動脈動乱の予防のための心臓再偏極化の表遺伝学

Sanjoy K Chowdhury1, Wei Liu1, Min Zi1

  • 1From Faculty of Biology, Medicine and Health (S.K.C., W.L., M.Z., Y.L., S.W., H.T., S.P., C.B.M., M.R.B., E.J.C., H.A.S., X.W.) and School of Physics and Astronomy (S.C., H.Z.), University of Manchester, United Kingdom; Atherosclerosis Research Centre, Nanjing Medical University, Jiangsu, China (Y.J.); Institute of Molecular Medicine, Peking University, Beijing, China (X.Z., R.X.); Case Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH (R.Z., X.L., M.K.J.); Department of Pharmacology, University of Oxford, United Kingdom (M.L.); and Department of Cardiology and Pneumology, University Medical Center Göttingen, Germany (L.C., K.G.).

Circulation
|December 1, 2016

PubMed で要約を見る

まとめ
この要約は機械生成です。

ミトゲン活性化キナーゼキナーゼ7欠乏症は,カリウムチャネル遺伝子発現を阻害することによって,心房不律のリスクを高めます. この経路をバルプロ酸で標的にすることで,新しい抗不律性療法が提供される可能性があります.

科学分野:

  • 心臓病科
  • 分子生物学
  • 遺伝学

背景:

  • 心臓発作による死亡の 主な原因です
  • 既存の抗不律薬はしばしば不律性の副作用があり,突然死のリスクが増加します.

研究 の 目的:

  • ミトゲン活性化キナーゼキナーゼ7 (MKK7) 欠乏症と心不全における不律症の脆弱性を関連付ける新しい調節メカニズムを調査する.
  • このメカニズムを標的とした 治療戦略を探求する

主な方法:

  • MKK7のノックアウトまたは過剰発現のマウスモデルを用いて,心筋縮および心不全における心律乱のメカニズムを研究した.
  • ヒトにおける関連性は,ヒト誘発性多能幹細胞由来心筋細胞を用いて評価された.
  • マウスモデルとヒトの細胞の両方で治療的介入をテストした.

主要な成果:

  • 過剰なストレスによりMK7の発現とリン酸化が低下し,非リン酸化ヒストン脱酸化-2とフィラミン-Aの核蓄積が生じます.
  • この複合体は,カリウムチャネル遺伝子プロモーターへのクリュッペルのような因子-4結合を妨害し,チャネル発現を減少させ,再極化遅延を引き起こす.
  • ヒストン減塩酵素-2 阻害剤であるバルプロ酸は,病的な心臓におけるカリウムチャネル発現を回復し,心室不律を減少させた.
キーワード:
心臓発作遺伝子発現の調節心不全製薬剤治療薬

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結論:

  • MKK7,HDAC2,FLNA,KLF4を含む新しい遺伝子調節経路が,心房不律の感受性の重要な決定因子として特定されました.
  • 病理的心房不律症の治療にバルプロ酸を抗不律剤として再利用することは,これらの発見によって支持されています.