免疫疾患におけるRNA分解酵素Regnase-1調節機構解明とその操作法の開発

RNA降解酶Regnase-1在免疫疾病中的调控机制的阐明及其操作方法的开发

基本信息

  • 批准号:
    19J23450
  • 负责人:
  • 金额:
    $ 1.98万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
  • 财政年份:
    2019
  • 资助国家:
    日本
  • 起止时间:
    2019-04-25 至 2022-03-31
  • 项目状态:
    已结题

项目摘要

Regnase-1 is a negative regulator of inflammation. It restricts immune responses by limiting the stability of inflammatory mRNAs (Il6, Il1b, Regnase-1, etc) through recognition of stem-loop (SL) structures in 3'untranslated regions (UTRs). In this project, we aimed to develop a therapeutic strategy to suppress inflammations through manipulating Regnase-1 availability. We achieved this by modulating the binding interaction between Regnase-1 and its SL structures, which was enabled by the simultaneous use of two antisense phosphorodiamidate morpholino oligonucleotides (MOs) targeting the right arms of the SL structure.Blocking Regnase-1 self-regulation by MOs successfully enhanced Regnase-1 expression in macrophages, which in turn decreased the expression of inflammatory transcripts targeted by Regnase-1. In addition, we observed that tissue-targeted delivery of Regnase-1-targeting-MOs attenuated inflammation and immune cell infiltration to disease sites in mouse models of acute respiratory distress syndrome, bleomycin-induced pulmonary fibrosis, and experimental autoimmune encephalomyelitis. At last, we found that Regnase-1 expression was inversely correlated with the disease severity of patients with multiple sclerosis, whereas MO treatment against human Regnase-1 SL structures successfully blunted their expression of pro-inflammatory genes upon LPS stimulation. Overall, our findings highlight that MO-mediated enhancement of Regnase-1 expression could serve as a novel therapeutic strategy to restrict inflammation and improve disease outcomes in mouse and human.
Regnase-1是炎症的负调节因子。它通过识别3 '非翻译区(UTR)中的茎环(SL)结构来限制炎性mRNA(IL 6、IL 1b、Regnase-1等)的稳定性,从而限制免疫应答。在这个项目中,我们的目标是开发一种治疗策略,通过操纵Regnase-1的可用性来抑制炎症。我们通过调节Regnase-1与其SL结构之间的结合相互作用来实现这一点,这是通过同时使用两个靶向SL结构右臂的反义磷酰二胺吗啉代寡核苷酸(MO)来实现的。通过MO阻断Regnase-1的自我调节成功地增强了巨噬细胞中Regnase-1的表达,这反过来又降低了Regnase-1靶向的炎症转录物的表达。此外,我们观察到Regnase-1靶向-MO的组织靶向递送在急性呼吸窘迫综合征、博来霉素诱导的肺纤维化和实验性自身免疫性脑脊髓炎的小鼠模型中减弱了炎症和免疫细胞向疾病部位的浸润。最后,我们发现Regnase-1表达与多发性硬化患者的疾病严重程度呈负相关,而针对人Regnase-1 SL结构的MO治疗成功地减弱了LPS刺激后促炎基因的表达。总的来说,我们的研究结果强调MO介导的Regnase-1表达增强可以作为一种新的治疗策略来限制炎症并改善小鼠和人类的疾病结局。

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Manipulation of Regnase-1 mRNA stability by antisense oligonucleotides alleviates inflammatory responses in pulmonary and autoimmune diseases
通过反义寡核苷酸操纵 Regnase-1 mRNA 稳定性可减轻肺部和自身免疫性疾病的炎症反应
  • DOI:
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ka Man Tse;Xiaotong Cui;Alexis Vandenbon;Keiko Yasuda;Takuya Uehata;Ayuko Sato;Tohru Tsujimura;Masanori Yoshinaga;Tatsusada Okuno;Yoshinari Nakatsuka;Osamu Takeuchi
  • 通讯作者:
    Osamu Takeuchi
Manipulating the expressions of Regnase-1 by stem-loop-targeting-antisense oligonucleotides to counteract inflammatory diseases
通过茎环靶向反义寡核苷酸操纵Regnase-1的表达来对抗炎症性疾病
  • DOI:
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ka Man Tse;Xiaotong Cui;Alexis Vandenbon;Takashi Mino;Takuya Uehata;Keioko Yasuda;Ayuko Sato;Tohru Tsujimura;Fabian Hia;Masanori Yoshinaga;Osamu Takeuchi
  • 通讯作者:
    Osamu Takeuchi
Enhancement of Regnase-1 expression with stem loop?targeting antisense oligonucleotides alleviates inflammatory diseases
茎环靶向反义寡核苷酸增强Regnase-1表达可减轻炎症性疾病
  • DOI:
    10.1126/scitranslmed.abo2137
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    17.1
  • 作者:
    Tse Ka Man;Vandenbon Alexis;Cui Xiaotong;Mino Takashi;Uehata Takuya;Yasuda Keiko;Sato Ayuko;Tsujimura Tohru;Hia Fabian;Yoshinaga Masanori;Kinoshita Makoto;Okuno Tatsusada;Takeuchi Osamu
  • 通讯作者:
    Takeuchi Osamu
Manipulation of Regnase-1 mRNA stability by morpholino-based antisense oligonucleotides alleviates inflammatory responses in pulmonary and autoimmune diseases
通过基于吗啉代的反义寡核苷酸操纵 Regnase-1 mRNA 稳定性可减轻肺部和自身免疫性疾病的炎症反应
  • DOI:
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ka Man Tse;Xiaotong Cui;Alexis Vandenbon;Keiko Yasuda;Takuya Uehata;Ayuko Sato;Tohru;Tsujimura;Takashi Mino;Masanori Yoshinaga;Tatsusada Okuno;Yoshinari Nakatsuka;Osamu Takeuchi
  • 通讯作者:
    Osamu Takeuchi
Manipulating the expression of Regnase-1 by antisense oligonucleotides to counteract inflammatory diseases
通过反义寡核苷酸操纵Regnase-1的表达来对抗炎症性疾病
  • DOI:
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ka Man Tse;Takashi Mino;Takuya Uehata;Keiko Yasuda;Masanori Yoshinaga;Osamu Takeuchi
  • 通讯作者:
    Osamu Takeuchi
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