Mechanosensitive M7G epitranscriptome in endothelial health and disease

机械敏感 M7G 表观转录组在内皮健康和疾病中的作用

基本信息

批准号：
10543139
负责人：
CHUAN HE
金额：
$ 69.7万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-22 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10543139
关键词：
Acceleration Address Artificial nanoparticles Atherosclerosis Biochemical Biological Process Blood Vessels Blood flow Cardiac Myocytes Cells Chemicals Data Development Disease Endothelium Functional disorder Gene Expression Goals Health Human In Vitro Knockout Mice Knowledge Link Malignant Neoplasms Maps Mediating Messenger RNA Methylation Methyltransferase Modification Molecular Mus Pathway interactions Proliferating RNA Regulation Resolution Risk Factors Role Site Technology Testing Therapeutic Vascular Cell Adhesion Molecule-1 Vascular Diseases Vascular Endothelium atherogenesis base cell type cohort epitranscriptome epitranscriptomics hemodynamics in vivo innovation mRNA Stability mechanotransduction methylome multidisciplinary nanomedicine nanoparticle novel novel therapeutic intervention restoration stem cell differentiation therapeutic effectiveness therapeutic evaluation transcriptome virtual

项目摘要

Project Summary RNA chemical modifications, collectively referred to as the “epitranscriptome”, have recently emerged as a novel layer of molecular control of gene expression. Most epitranscriptomic studies address N6- methyladenosine (m6A) of mRNA in human cancers. The molecular identity of endothelial mRNA epitranscriptome and its potential role in regulating vascular functions remains a major knowledge gap. Recent studies suggested that mammalian mRNAs are broadly chemically modified and mRNA modifications occur in a cell-type and cell-state dependent manner. N6-methyladenosine (m6A), the most abundant internal (outside of the 5’ cap) methylation in mammalian mRNA, has been linked to critical biological processes such as proliferation, development, and stem cell differentiation. Only few recent studies addressed the potential role of mRNA m6A in cardiomyocyte remodeling and endothelial activation. We recently discovered the presence of a new chemical modification, N7-methylguanosine (m7G) in mammalian mRNA. Systematic m7G mapping in endothelial mRNA and its potential role in vascular pathophysiology is an unexplored territory. Vascular endothelium is dynamically regulated by blood flow via mechano-transduction mechanisms. Endothelial activation by disturbed flow contributes to a wide range of vascular diseases. Atherosclerosis preferentially develops in arterial sites where endothelium is activated by local disturbed flow whereas unidirectional flow promotes endothelial health. Current atherosclerosis therapies mainly target systematic risk factors but not the vasculature per se. This underscores the significance and unique opportunity to identify and target novel mechanosensitive mechanisms in vascular endothelium. We have generated very strong data demonstrating that the mRNA m7G is dynamically regulated in endothelium by hemodynamics. Unidirectional flow (UF) markedly increases m7G but not m6A in endothelial mRNAs. Moreover, Methyltransferase-Like 7A (METTL7A) is a novel m7G writer governing the UF-induced mRNA m7G methylation in endothelium. The overall goal of this project is to delineate the novel molecular mechanisms by which mechano-sensitive METTL7A governs endothelial mRNA m7G and regulates vascular functions in vitro and in vivo. Moreover, we will devise innovative precision nanomedicine approaches targeting METTL7A-mediated pathways to treat atherosclerosis.

项目概要 RNA化学修饰，统称为“外转录组”，最近出现作为基因表达分子控制的新层，大多数表观转录组研究都针对 N6-。人类癌症中 mRNA 的甲基腺苷 (m6A) 内皮 mRNA 的分子特性。表观转录组及其在调节血管功能中的潜在作用仍然是一个主要的知识空白。最近的研究表明，哺乳动物的 mRNA 被广泛化学修饰，并且 mRNA 修饰以细胞类型和细胞状态依赖性方式发生。哺乳动物 mRNA 中丰富的内部（5’帽外）甲基化与关键的生物相关最近只有少数研究涉及增殖、发育和干细胞分化等过程。我们最近研究了 mRNA m6A 在心肌细胞重塑和内皮激活中的潜在作用。发现哺乳动物 mRNA 中存在新的化学修饰 N7-甲基鸟苷 (m7G)。内皮 mRNA 的系统性 m7G 定位及其在血管病理生理学中的潜在作用是未开发的领域。血管内皮通过机械传导机制受血流动态调节。血流紊乱引起的内皮激活会导致多种血管疾病。优先在动脉部位发展，其中内皮细胞被局部扰动的血流激活，而单向流动促进内皮健康当前的动脉粥样硬化治疗主要针对系统风险。这强调了识别和识别的重要性和独特的机会。针对血管内皮的新型机械敏感机制。我们已经生成了非常有力的数据，证明 mRNA m7G 在单向血流 (UF) 显着增加内皮细胞中的 m7G，但不增加 m6A。此外，甲基转移酶样 7A (METTL7A) 是一种新型 m7G 写入器，控制 UF 诱导的该项目的总体目标是描绘内皮细胞中的 mRNA m7G 甲基化。机械敏感性 METTL7A 控制内皮 mRNA m7G 并调节血管的机制此外，我们将针对目标设计创新的精密纳米医学方法。 METTL7A 介导的治疗动脉粥样硬化的途径。