NAMPT媒介のNAD+バイオシンセシスの経由で循環する循環時時計のフィードバックサイクル.
Kathryn Moynihan Ramsey1, Jun Yoshino, Cynthia S Brace
1Department of Medicine, Northwestern University Feinberg School of Medicine, 2200 Campus Drive, Evanston, IL 60208-3500, USA.
Science (New York, N.Y.)
|March 21, 2009
まとめ
ネズミは,ニコチナミドアデニン・ディヌクレオチド (NAD+) 生合成酵素NAMPTとNAD+レベルにおける毎日のリズムを示しています. この発見は,NAMPT/NAD+とSIRT1/CLOCK:BMAL1を結びつけるフィードバックループを明らかにし,昼間の時計の調節に影響を与えています.
科学分野:
- クロノバイオロジーはクロノバイオロジーを用います.
- メタボリズムは
- 分子生物学は分子生物学である.
背景:
- 昼間の時計は,トランスクリプション・トランスレーション・フィードバック・ループを通じて,生理学的プロセスを日々の光暗サイクルと同期させます.
- ニコチナミドアデニン・ディヌクレオチド (NAD+) は,エネルギー代謝と細胞プロセスに関与する重要な代謝物質です.
- 酵素NAMPTは,哺乳類におけるNAD+生物合成の速度を制限する.
研究 の 目的:
- 昼間の時計機構によるNAMPTとNAD+レベルの調節を調査する.
- NAMPT/NAD+とコアクロックコンポーネントを含むフィードバックメカニズムを解明する.
主な方法:
- マウスモデルを用いて,昼間の振動を研究した.
- NAMPTの遺伝子および薬理学的阻害を働かせました.
- 時計遺伝子 (例えばPer2) とタンパク質複合体 (例えばCLOCK:BMAL1, SIRT1) の発現を分析した.
主要な成果:
- NAMPTとNAD+のレベルが,コアクロックの構成要素によって調節される,マウスの昼夜振動を示すことを実証した.
- NAMPTの阻害は,CLOCK:BMAL1をSIRT1媒介の抑制から解放することによってPer2の振動を強化することを示した.
- 転写因子 CLOCK が Nampt 発現を向上調節し,フィードバックループを確立することを特定しました.
結論:
- NAMPT/NAD+経路は哺乳類の昼夜時計に統合されています.
- NAMPT/NAD+とSIRT1/CLOCK:BMAL1複合体との間に新しいフィードバックループが存在し,昼夜リズムに影響を与えています.
- この相互作用は,代謝と昼夜間のタイミングの間の分子リンクを提供します.
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