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ビタミンDはBAF複合体を切り替えてβ細胞を保護する

Zong Wei¹, Eiji Yoshihara¹, Nanhai He¹

¹Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

|May 15, 2018

まとめ

ビタミンD受容体 (VDR) は,2型糖尿病 (T2D) のベータ細胞を炎症と機能障害から守る上で重要な役割を果たします. VDR-クロマチンの相互作用をターゲットにすることで,T2Dの新たな治療戦略が提供されます.

科学分野:

内分泌学
分子生物学
免疫学

背景:

2型糖尿病 (T2D) は,炎症とインスリン抵抗性によって引き起こされるベータ細胞機能障害によって特徴付けられます.
ベータ細胞の枯渇を防ぐことは,T2Dの進行管理における重要な治療上の障害です.

研究の目的:

ビタミンD受容体 (VDR) が炎症とベータ細胞生存を調節する役割を調査する.
VDRに関連したタンパク質複合体とT2Dの文脈におけるその機能を特定する.

主な方法:

ブロモドメインタンパク質 (BRD7,BRD9) とクロマチン再構成複合体 (PBAF,BAF) とのVDR相互作用を調査した.
クロマチンのアクセシビリティと強化剤の活性に対するVDRの全ゲノム効果を分析した.
T2DのマウスモデルでBRD9の薬理学的抑制を活用した.

主要な成果:

VDRは炎症とベータ細胞の生存を調節する.
VDRは,アセチル化とブロモドメインタンパク質によって媒介されるPBAF染色体改造複合体と関連しています.
リガンド結合のVDRはPBAF結合を促進し,抗炎症効果をもたらす.
BRD9の阻害はPBAF- VDR関連性を高め,ベータ細胞の機能を回復し,糖尿病のマウスの高血糖症を改善します.

結論:

T2Dにおけるベータ細胞生存に不可欠な未定のVDR依存の転写経路を特定した.
VDR:PBAF/BAF関連はT2D治療の潜在的な治療目標を表しています.

キーワード:

BAF複合体 BRD9 について CRISPRスクリーニング PBAF複合体 VDR についてクロマチンの改造糖尿病炎症核受容体 β セル

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