The mechanical regulation of microRNA epitranscriptomics in heart failure

microRNA表观转录组学在心力衰竭中的机械调控

• 批准号: EP/X023729/1
• 负责人: Fabiana Martino
• 金额: $ 26万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX023729%2F1
• 关键词: mechanical; regulation; microRNA; epitranscriptomics; heart

Despite advances in therapies and prevention, heart failure (HF) remains a leading cause of morbidity and mortality worldwide. The heart is exposed to mechanical forces and constantly adapts to its environment in a process known as cardiac remodelling. Excessive mechanical load is a major driver of pathological cardiac remodelling, progressively leading to HF. A set of microRNAs (miRs) are responsive to mechanical forces (mechanomiRs) and contribute to heart pathophysiology and HF. Epitranscriptomics (i.e., the biochemical modification of the RNA) is emerging as a new layer of gene expression regulation affecting both coding and non-coding RNAs. N6-adenosine RNA methylation (m6A) regulate the processing of miR transcripts (pri-miRs) to functional miRs, promoting angiogenesis and cardiac repair after myocardial infarction. However, dysregulation of m6A reportedly contributes to HF. The role played by epitranscriptomics in heart mechanical responses and mechanomiR regulation have not yet been investigated, although crucial to inform transformative therapeutics. Epi-mecHEART aims to unveil the mechanically induced epitranscriptomic mechanisms leading to HF, focussing on mechanomiRs. Combining "living myocardial slice" and computational technologies (available at the host lab) with molecular techniques and biomechanical tools, I will i) identify the mechanosensitive N6-methylation responses in cardiomyocytes subjected to mechanical overload; ii) unveil how mechanical overload modulates the N6-methylation profile of both pri-miRs and miR-mRNA targets; iii) investigate how the mechanically induced N6-methylation on mRNAs impacts miR-targeting function iv) validate the clinical relevance of mechanically-induced N6-methylation changes in HF, by use of clinical samples. Targeting N6-methylation represents a transformative strategy to support the adaptation of the heart to increased workload, thus preventing HF.

尽管在治疗和预防方面取得了进展，但心力衰竭（HF）仍然是全球发病率和死亡率的主要原因。心脏暴露于机械力，并在称为心脏重塑的过程中不断适应其环境。过度的机械负荷是病理性心脏重塑的主要驱动力，逐渐导致HF。一组microRNA（miR）响应于机械力（mechanomiR）并促成心脏病理生理学和HF。表位转录组学（即，RNA的生物化学修饰）作为影响编码和非编码RNA的基因表达调节的新层而出现。N6-腺苷RNA甲基化（m6 A）调节miR转录物（pri-miR）加工成功能性miR，促进心肌梗死后的血管生成和心脏修复。然而，据报道，m6 A的失调促成HF。epitranscriptomics在心脏机械反应和mechanomiR调节中所起的作用尚未研究，尽管对于告知变革性治疗至关重要。Epi-mecHEART旨在揭示导致HF的机械诱导的epitranscriptomic机制，重点是mechanomiR。结合“活心肌切片”和计算技术（可在主机实验室获得）利用分子技术和生物力学工具，我将i）鉴定机械过载下心肌细胞中的机械敏感性N6甲基化反应; ii）揭示机械过载如何调节pri-miRs和miR-mRNA靶点的N6甲基化谱; iii）研究mRNA上机械诱导的N6-甲基化如何影响miR靶向功能iv）通过使用临床样品验证HF中机械诱导的N6-甲基化变化的临床相关性。靶向N6-甲基化代表了一种支持心脏适应增加的工作负荷的变革性策略，从而预防HF。