空間時間的なマルチオミックマッピングは,大動脈弁の分子アトラスを生成し,病気を駆動するネットワークを明らかにします
Florian Schlotter1, Arda Halu1,2, Shinji Goto1
1Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine (F.S., A.H., S.G., M.C.B., L.H.L., H.H., J.D.H., P.V., T.P., M.A.R., M.A., S.A.S., E.A.).
Circulation
|March 29, 2018
まとめ
カルシフ性大動脈弁疾患 (CAVD) には薬学的な治療法がない. この研究では,CAVDの進行を促す分子ネットワークと細胞行動が特定され,この心臓病の新たな診断と治療目標を提供しました.
科学分野:
- 心血管生物学
- 分子医学
- システム生物学
背景:
- カルシフ性大動脈弁疾患 (CAVD) は進行する心臓疾患で,現在薬理学的治療法はないため,侵入的弁置換が必要である.
- 複数の段階と組織層にわたるCAVDの複雑な病理学を理解することは,診断と治療法の開発に不可欠です.
- 大動脈弁のユニークな細胞および細胞外マトリックス特性は,CAVDの研究に重大な課題をもたらす.
研究 の 目的:
- カルシフ性大動脈弁疾患 (CAVD) の進行の基礎にある分子機構と規制ネットワークを調査する.
- 異なる病理的段階と 動脈弁の解剖学的層に 異なる分子シグネチャーを識別する
- 弁間細胞のカルシフィケーションの可能性と刺激に対するタンパク質反応を調査する.
主な方法:
- トランスクリプトミクスとプロテオミクスを含むマルチオミクスアプローチをヒトの静脈性大動脈弁に活用した.
- 近赤外線分子イメージングとレーザー捕捉マイクロ解剖を用いて,段階と層の固有のサンプル分割を行っています.
- 様々な刺激下でのカルシフィケーションの可能性とプロテオミクプロファイルを評価するために,サイド特異的な細胞培養を確立した.
- 重要なタンパク質と疾患の関連性を特定するために 分子相互作用ネットワークを構築した.
主要な成果:
- 疾患のないCAVD,線維性CAVD,および性CAVDの全般的な遺伝子およびタンパク質発現パターンを区別した.
- 大動脈弁の微層で独特のプロテオームプロファイルが特定され,スポンジオザ層の弁間細胞のマーカーとしてグリアル線維酸性タンパク質が使用されました.
- CAVDの進行過程で,滑らかな筋肉細胞の活性化,炎症,および化経路の増加が観察されました.
- 繊維菌由来弁間細胞は,室内細胞と比較してインビトロではより高いカルシフィケーションポテンシャルを示した.
- タンパク質とタンパク質の相互作用ネットワークは,炎症性および線維性疾患との重要な関連性を明らかにした.
結論:
- CAVDにおける分子規制ネットワークをマッピングするための空間的および時間的に解決されたマルチオミックスの戦略を開発した.
- CAVDの病原性を駆動する新しい分子経路と細胞行動が特定されました.
- 心血管疾患におけるオミクス研究に適用できる体系的な疾患本体論を確立し,新しい治療戦略の道を開いた.
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