アポトーシスとネクロトーシスの抑制による腫瘍ネクロシス因子受容体関連因子2の心臓保護作用
Xiaoyun Guo1, Haifeng Yin1, Lei Li1
1From Department of Physiology and Biophysics, University of Washington, Seattle.
Circulation
|June 3, 2017
まとめ
腫瘍死因受容体関連因子2 (Traf2) は死滅を抑制し,心不全を予防する. ネズミのTraf2を削除すると心不全が起こりますが,ネクロプトーシスレギュレータを復元するとフェノタイプが回復します.
科学分野:
- 心血管生物学
- 細胞 死 の 経路
- 分子心臓科
背景:
- アポトーシス,ミトコンドリア媒介性ネクロシス,そしてネクロプトシスを含むプログラム細胞死は,不全性心損傷,病的な心改造,心不全において極めて重要です.
- アポプトーシスとミトコンドリア媒介性死滅はよく知られていますが,死滅を調節するメカニズムと心不全の病原性におけるその役割は不明です.
研究 の 目的:
- 腫瘍死滅因子受容体関連因子2 (Traf2) が心筋死滅と心筋再形成を調節する役割を調査する.
- Traf2 が心臓における死滅シグナル伝達に影響を与える分子メカニズムを解明する.
主な方法:
- トラフ2の心臓特異的削除による遺伝子マウスモデルを使用した.
- トラフ2の死滅シグナル伝達経路の調節作用を定義するために分子および細胞生物学の研究を行った.
- TNFR1とRIP3の消去が心臓のフェノタイプに与える影響を調べました.
主要な成果:
- Traf2の心臓特異的消去は ネズミの死滅性細胞死亡,病変性再構成,心不全を引き起こした.
- トラフ2欠乏症のマウスでは,プラズマ腫瘍死滅因子α値が上昇した.
- TNFR1またはRIP3の遺伝的消去は,Traf2の消去に関連した心臓再構成および機能不全のフェノタイプを大きく救出し,ネクロプトーシスの重要な役割を確認しました.
結論:
- トラフ2媒介のNFκB独立の生存経路が特定され,死細胞の信号伝達を抑制する.
- この経路は,病的な心改変と心不全の治療のための新たな治療目標を表しています.
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