Potential therapeutic application of epigenetic mechanisms involved in the septic pathology

脓毒症病理学表观遗传机制的潜在治疗应用

• 批准号: 23590298
• 负责人: HATTORI Yuichi
• 金额: $ 3.41万
• 依托单位: University of Toyama
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23590298/
• 关键词: エピジェネティクス; 脱アセチル化酵素; 敗血症; 急性肺傷害; 炎症性サイトカイン; アポトーシス; 転写因子; エピジェネティックス; レスベラトロール; SIRT1

Epigenetic programming, dynamically regulated by histone acetylation, may play a key role in the pathophysiology of sepsis. Mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis were used to examine whether histone deacetylase (HDAC) can contribute to sepsis-associated inflammation and apoptosis. Histone H3 and H4 acetylation levels were increased, and HDAC1, HDAC2, and HDAC3 protein levels were decreased in lungs after CLP. The results with HDAC inhibitors indicated that they are a unique agent to prevent cell apoptosis in sepsis at their doses that do not improve inflammatory features. This study also represents the down-regulation of HDACs in sepsis, but suggest that imbalance in histone acetylation may play a contributory role in expression or repression of genes involved in septic cell apoptosis.

表观遗传编程，由组蛋白乙酰化动态调节，可能在脓毒症的病理生理中发挥关键作用。采用盲肠结扎穿刺（CLP）诱导的多微生物脓毒症小鼠，研究组蛋白去乙酰化酶（HDAC）是否与脓毒症相关的炎症和细胞凋亡有关。CLP后肺组蛋白H3、H4乙酰化水平升高，HDAC1、HDAC2、HDAC3蛋白水平降低。HDAC抑制剂的结果表明，它们是一种独特的药物，可以在不改善炎症特征的剂量下防止脓毒症中的细胞凋亡。本研究也表明hdac在脓毒症中下调，但提示组蛋白乙酰化失衡可能在脓毒症细胞凋亡相关基因的表达或抑制中发挥作用。

项目成果

Protection from lethal cell death in cecal ligation and puncture-induced sepsis mouse model by in vivo delivery of FADD siRNA. In : Targets in Gene Therapy(ed. by Yongping You)

通过体内递送 FADD siRNA，防止盲肠结扎和穿刺诱导的脓毒症小鼠模型中的致命细胞死亡。

• 发表时间: 2011
• 作者: Hattori Y;Matsuda N
• 通讯作者: Matsuda N

新規HDAC阻害薬CG200745は敗血症アポトーシスを阻止する

新型 HDAC 抑制剂 CG200745 阻断脓毒症细胞凋亡

• 发表时间: 2012
• 作者: 武部真理子;大石博史;青木優太;高階道徳;冨田賢吾;田口久美子;横尾宏毅;山崎光章;服部裕一
• 通讯作者: 服部裕一

Protection from both inflammation and apoptosis as a novel therapeutic strategy for severe sepsis."All about Shock"

防止炎症和细胞凋亡作为严重脓毒症的新型治疗策略。“All about Shock”

• 发表时间: 2013
• 作者: Takano K.;Yamamoto S.;Tomita K.;Takashina M.;Yokoo H.;Matsuda N.;Takano Y.;and Hattori Y.;Yuichi Hattori
• 通讯作者: Yuichi Hattori

敗血症の病理学的変化におけるエピジェネティックス制御の関与

表观遗传调控参与脓毒症病理变化

• 发表时间: 2013
• 作者: 武部真理子;大石博史;青木優太;高階道徳;冨田賢吾;田口久美子;横尾宏毅;山崎光章;服部裕一
• 通讯作者: 服部裕一

Possible role of epigenetic modifications in the pathology of sepsis.

表观遗传修饰在脓毒症病理学中的可能作用。

• 发表时间: 2013
• 作者: Takebe M,Oishi H,Aoki Y,Hattori Y;Yamazaki M
• 通讯作者: Yamazaki M