Epigenetic gene repression in pulmonary fibrosis

肺纤维化中的表观遗传基因抑制

基本信息

  • 批准号:
    10432006
  • 负责人:
  • 金额:
    $ 41.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-07-01 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Pulmonary fibrosis represents an increasing cause of mortality worldwide and despite decades of investigation, considerable uncertainty exists as how this disease initiates and progresses. While multiple fibrogenic molecules have been found to drive aberrant matrix deposition, the mechanisms responsible for maintaining persistent and self-sustaining fibrogenesis are largely unknown. Targeting mechanisms that perpetuate the pathological state of fibroblasts during disease progression may serve as an attractive therapeutic strategy to halt lung fibrosis. The current proposal addresses the role of epigenetic gene repression in regulating fibroblast activation and lung fibrosis development. We will investigate the role of histone 3 lysine 9 methylation (H3K9me) as an important epigenetic modification that represses the transcription of genes essential to maintaining or returning lung fibroblasts to an anti-fibrotic or quiescent inactive state. Our preliminary data demonstrate that inhibition of H3K9 methylation by targeting the H3K9 methyltransferase G9a or the epigenetic reader CBX5 potently inhibits fibroblast activation by fibrogenic stimuli. Mechanistically, our data demonstrate that both G9a and CBX5 are directly involved in repressing PGC1, a master regulator of mitochondria metabolism significantly downregulated in diseased lung fibroblasts. Loss of PGC1 expression promotes fibroblast activation, while restoring PGC1 via epigenetic mechanisms reverses fibroblast activation. We will use loss of function strategies to target the epigenetic regulators CBX5 and G9a to investigate their mechanistic roles in switching fibroblasts between activated and quiescence states. Using mouse genetics approaches we will investigate the benefits of inhibiting H3K9 methylation in halting disease progression in bleomycin-induced lung fibrosis models. As our preliminary data strongly support an anti-fibrotic function for PGC1 during lung fibroblast activation in vitro, in this proposal we will further characterize its anti-fibrotic function and evaluate upstream and downstream transcriptional network that mediate its anti-fibrotic functions. Taken together, the proposed research studies will reveal critical epigenetic targets for therapeutic interventions aimed at halting or reversing the progression of pulmonary fibrosis.
项目概要 肺纤维化是全世界日益严重的死亡原因,尽管经过了数十年的研究, 这种疾病如何发生和发展存在很大的不确定性。虽然多发性纤维化 已发现分子可驱动异常基质沉积,该机制负责维持 持续性和自我维持的纤维发生在很大程度上是未知的。使目标永久化的机制 疾病进展过程中成纤维细胞的病理状态可能作为一种有吸引力的治疗策略 阻止肺纤维化。目前的提案讨论了表观遗传基因抑制在调节成纤维细胞中的作用 激活和肺纤维化发展。我们将研究组蛋白 3 赖氨酸 9 甲基化的作用 (H3K9me) 作为一种重要的表观遗传修饰,可抑制基因的转录 维持或恢复肺成纤维细胞至抗纤维化或静止非活性状态。我们的初步数据 证明通过靶向 H3K9 甲基转移酶 G9a 或表观遗传抑制 H3K9 甲基化 阅读器 CBX5 有效抑制纤维形成刺激引起的成纤维细胞活化。从机制上讲,我们的数据表明 G9a 和 CBX5 都直接参与抑制 PGC1(线粒体的主要调节因子) 患病肺成纤维细胞的代谢显着下调。 PGC1α表达缺失促进 成纤维细胞活化,同时通过表观遗传机制恢复 PGC1 可逆转成纤维细胞活化。我们将 使用功能丧失策略来靶向表观遗传调节因子 CBX5 和 G9a,以研究其作用 成纤维细胞在激活状态和静止状态之间切换的机制作用。利用小鼠遗传学 我们将研究抑制 H3K9 甲基化在阻止疾病进展方面的益处 博莱霉素诱导的肺纤维化模型。由于我们的初步数据强烈支持抗纤维化功能 PGC1在体外肺成纤维细胞激活过程中,在本提案中我们将进一步表征其抗纤维化作用 功能并评估介导其抗纤维化功能的上游和下游转录网络。 总而言之,拟议的研究将揭示治疗的关键表观遗传靶点 旨在阻止或逆转肺纤维化进展的干预措施。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation.
  • DOI:
    10.1038/s41419-021-04439-4
  • 发表时间:
    2021-12-17
  • 期刊:
  • 影响因子:
    9
  • 作者:
    Ring NAR;Volpe MC;Stepišnik T;Mamolo MG;Panov P;Kocev D;Vodret S;Fortuna S;Calabretti A;Rehman M;Colliva A;Marchesan P;Camparini L;Marcuzzo T;Bussani R;Scarabellotto S;Confalonieri M;Pham TX;Ligresti G;Caporarello N;Loffredo FS;Zampieri D;Džeroski S;Zacchigna S
  • 通讯作者:
    Zacchigna S
Kidney endothelial cell heterogeneity, angiocrine activity and paracrine regulatory mechanisms.
肾内皮细胞异质性、血管分泌活性和旁分泌调节机制。
  • DOI:
    10.1016/j.vph.2022.107139
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    4
  • 作者:
    Ribatti,Domenico;Ligresti,Giovanni;Nicosia,RobertoF
  • 通讯作者:
    Nicosia,RobertoF
Survivin IPF: Targeting Cellular Metabolism to Promote Apoptosis in IPF Fibroblasts.
Survivin IPF:靶向细胞代谢促进 IPF 成纤维细胞凋亡。
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Giovanni Ligresti其他文献

Giovanni Ligresti的其他文献

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{{ truncateString('Giovanni Ligresti', 18)}}的其他基金

Targeting vascular dysfunction to promote lung repair and fibrosis resolution
针对血管功能障碍促进肺修复和纤维化消退
  • 批准号:
    10444342
  • 财政年份:
    2022
  • 资助金额:
    $ 41.25万
  • 项目类别:
Targeting vascular dysfunction to promote lung repair and fibrosis resolution
针对血管功能障碍促进肺修复和纤维化消退
  • 批准号:
    10584589
  • 财政年份:
    2022
  • 资助金额:
    $ 41.25万
  • 项目类别:
Epigenetic gene repression in pulmonary fibrosis
肺纤维化中的表观遗传基因抑制
  • 批准号:
    10020431
  • 财政年份:
    2018
  • 资助金额:
    $ 41.25万
  • 项目类别:
Epigenetic gene repression in pulmonary fibrosis
肺纤维化中的表观遗传基因抑制
  • 批准号:
    10197207
  • 财政年份:
    2018
  • 资助金额:
    $ 41.25万
  • 项目类别:
Epigenetic gene repression in pulmonary fibrosis
肺纤维化中的表观遗传基因抑制
  • 批准号:
    9924000
  • 财政年份:
    2018
  • 资助金额:
    $ 41.25万
  • 项目类别:
Epigenetic gene repression in pulmonary fibrosis
肺纤维化中的表观遗传基因抑制
  • 批准号:
    9573741
  • 财政年份:
    2018
  • 资助金额:
    $ 41.25万
  • 项目类别:

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