Mitochondrial R-loop in sepsis-induced cardiomyopathy

脓毒症诱发的心肌病中的线粒体 R 环

基本信息

  • 批准号:
    10586871
  • 负责人:
  • 金额:
    $ 44.52万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-12 至 2027-12-31
  • 项目状态:
    未结题

项目摘要

Abstract Sepsis is a life-threatening organ dysfunction that induces a multitude of defects in immunity for sustained periods of time after clinical recovery that is closely correlated with long-term mortality associated with septic cardiomyopathy. Although immune-based therapies have been designed to suppress inflammatory responses, this strategy alone has marginal benefits for sepsis patients, as the dominant molecular drivers of septic cardiomyopathy-associated inflammation remain unclear. As our knowledge of mitochondria advances, we first investigated a previously underappreciated activator in inflammation and disease progression, mitochondrial R- loop (RNA:DNA hybrid) termed mtR-loop, and discovered aberrant accumulation in cardiomyocytes after sepsis. The contributory role of mtR-loop toward cardiomyopathy post sepsis was documented in a pilot study showing that unresolved mtR-loop is pathological, which is linked to not only mitochondrial genome instability, but also unresolved chronic inflammation through activating both non-immune cells (cardiomyocytes) and immune cells (macrophages). Most importantly, these cardiomyocyte-derived mtR-loop could translocate to extracellular compartments and were sensed by macrophages in the heart to fuel a fata response to sepsis. This proposal will test the hypothesis that septic cardiomyocyte derived mtR-loop are the central hub that connect various pathways of the immune response in the inflammatory network. If identified, mtR-loop inhibition will be explored as a potential novel cardio-protector against stress. To this, we will employ genetic tools combined with reporter mice to monitor mtR-loop translocation within cells, track mtR-loop uptake by immune cells, define the mechanism underlying mtR-loop intercellular communication and initiated inflammation, and characterize the infiltrating cells. Mechanistically, our pilot data first showed that the SUMOlyation-dependent packaging of lncRNA (lncRP11) into mitochondria, which hybrids with mtDNA to form mtR-loop (lncRNA:mtDNA structure). Those lncRNA-associated mtR-loop acts an upstream trigger of inflammatory network in septic hearts. Based on these initial findings, we hypothesize that suppression of lncRP11 transcription can reduce or prevent cardiac dysfunction in post-sepsis by directly reversing or ameliorating inflammation associated with cardiomyocyte failure. Specifically, by 3D genome mapping, the physical contact of enhancer and promoter, but not their activities, was identified to regulate lncRP11 transcription in septic hearts. Interestingly, this is largely due to loss of CTCF-mediated insulator between lncRP11 promoter and enhancer. In addition, the CTCF binding on the insulator is sensitive to DNA methylation. Thus, we propose that gain of CTCF-mediated insulator by epigenetic editing tool could block enhancer/promoter interaction and thus silence lncRP11 transcription. Results of these studies will be used to develop a viable therapeutic approach using targeted epigenetic editing, which can efficiently resolve lncRP11-associated pathological mtR-loop and thereby ameliorate stress-induced cardiac damage and reduce the mortality and morbidity of patients with septic cardiomyopathy.
摘要 脓毒症是一种危及生命的器官功能障碍,其引起免疫系统的大量缺陷, 临床恢复后的时间与脓毒性相关的长期死亡率密切相关, 心肌病尽管基于免疫的疗法被设计用于抑制炎症反应, 作为脓毒症的主要分子驱动因素, 心肌病相关炎症仍不清楚。随着我们对线粒体知识的进步,我们首先 研究了以前在炎症和疾病进展中被低估的激活剂,线粒体R- 环(RNA:DNA杂合体)称为mtR-loop,并发现败血症后心肌细胞中异常积聚。 在一项初步研究中记录了mtR环对脓毒症后心肌病的贡献作用, 未解决的mtR环是病理性的,这不仅与线粒体基因组的不稳定性有关, 通过激活非免疫细胞(心肌细胞)和免疫细胞, (巨噬细胞)。最重要的是,这些心肌细胞来源的mtR环可以移位到细胞外, 在心脏中的巨噬细胞感受到FATA对脓毒症的反应。这项建议 我们将检验这一假设,即脓毒症心肌细胞衍生的mtR环是连接各种 炎症网络中的免疫反应途径。如果确定,将探索mtR环抑制 作为一种潜在的新型抗应激心脏保护剂。为此,我们将采用遗传工具结合报告基因的方法, 小鼠监测细胞内的mtR环易位,跟踪免疫细胞对mtR环的摄取, mtR环细胞间通讯和引发炎症的机制,并表征 浸润细胞从机制上讲,我们的试验数据首先表明,SUMO依赖性包装的 lncRNA(lncRP 11)进入线粒体,与mtDNA杂交形成mtDNA环(lncRNA:mtDNA结构)。 这些lncRNA相关的mtR环在脓毒症心脏中充当炎症网络的上游触发器。基于 基于这些初步的发现,我们假设抑制lncRP 11的转录可以减少或阻止心脏 通过直接逆转或改善与心肌细胞相关的炎症来治疗脓毒症后的功能障碍 失败具体地,通过3D基因组作图,增强子和启动子的物理接触,但不是它们的物理接触。 活动,被确定可调节脓毒症心脏中lncRP 11的转录。有趣的是,这在很大程度上是由于损失 在lncRP 11启动子和增强子之间存在CTCF介导的绝缘子。此外,CTCF结合在 绝缘子对DNA甲基化敏感。因此,我们提出通过表观遗传获得CTCF介导的绝缘子, 编辑工具可以阻断增强子/启动子相互作用,从而沉默lncRP 11转录。结果进行 研究将用于开发一种可行的治疗方法,使用靶向表观遗传编辑, 有效地解决lncRP 11相关的病理性mtR环,从而改善应激诱导的心脏 降低脓毒性心肌病患者的死亡率和发病率。

项目成果

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Wei Huang其他文献

A new colorimetric and fluorescent ratiometric sensors for Hg2+ based on 4-pyren-1-yl-pyrimidine
基于 4-芘-1-基-嘧啶的新型 Hg2 比色和荧光比率传感器
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Qunbo Mei;Jiena Weng;Qidan Ling;Quli Fan;Wei Huang
  • 通讯作者:
    Wei Huang

Wei Huang的其他文献

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{{ truncateString('Wei Huang', 18)}}的其他基金

Core 1: Integrated Pathology and Radiology Core (iPRC)
核心 1:综合病理学和放射学核心 (iPRC)
  • 批准号:
    10555403
  • 财政年份:
    2023
  • 资助金额:
    $ 44.52万
  • 项目类别:
Causal role of higher-order thalamo-cortical oscillations in sustained attention
高阶丘脑皮质振荡在持续注意力中的因果作用
  • 批准号:
    10199754
  • 财政年份:
    2019
  • 资助金额:
    $ 44.52万
  • 项目类别:

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