CARDINAL - Cardiomyocyte-derived vesicular non coding RNAs and post-ischemic cardiac remodeling

CARDINAL - 心肌细胞来源的囊泡非编码 RNA 和缺血后心脏重塑

• 批准号: 316872437
• 负责人: Professor Dr. Thomas Thum, Ph.D.
• 金额: --
• 依托单位: Institut für Molekulare und Translationale Therapiestrategien
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/316872437?language=en
• 关键词: CARDINAL; Cardiomyocyte; derived; vesicular; non

Cardiovascular diseases (CVD) are the main cause of mortality in nearly all European countries despite the best state-of-the-art treatments. Diabetes, a global health concern with an estimated 347 million affected people worldwide and a projected 50% increase in incidence during the next decade, increases by about 3-fold the risk of CVD. A striking failure in the treatment of diabetes is the inability of lifestyle- or drug-based interventions to impact on the excess risk of diabetes-induced adverse ventricular remodelling and cardiac dysfunction. Hence, efforts are directed towards pivotal pathways shaping cardiac homeostasis. After myocardial infarction, the cardiac tissue release several soluble chemokines, cytokines, and growth factors, which induce inflammatory response to shape the repair process. However, there are several open questions about how the myocardium initiates the local repair process or how it manipulates inflammatory reaction. In addition, fibroblast-induced fibrosis is also an integral component of cardiac remodelling and informations are lacking concerning the nonpermissive mechanisms induced by the ischemic milieu. Our hypothesis is that extracellular vesicles (EVs) are released locally in the heart following myocardial infarction and that the transfer of their non-coding RNA content affects the local inflammatory response as well as fibroblast-dependent activity and subsequently repair mechanisms. This proposal aims at 1-characterizing and analyzing the non-coding RNA (microRNAs and long non-coding RNAs) cargo of EVs isolated from infarcted myocardium in a type-2 diabetic murine model, from cultured cardiomyocytes cell line and induced pluripotent cell-derived cardiomyocytes, 2- identifying and exploring the impact of EV transfer to target cells in vitro and in vivo in the context of diabetes, and identifying targets of functionally transported non-coding RNAs to recipient cells, including fibroblasts and inflammatory cells, 3- designing therapeutic approaches by either delivering beneficial noncoding RNA oligonucleotides using synthetic liposomes or inhibiting detrimental specific noncoding RNAs using LNA/GapmeRs. This projects brings together one german and two french partners with leading expertise in inflammation and fibrosis after myocardial infarction and in extracellular vesicle and noncoding RNA analysis. Their preliminary data show specific noncoding RNA packaging into extracellular vesicles of cardiomyocyte origin produced either in vitro or in vivo following myocardial infarction, and vesicle targeting to recipients fibroblasts and inflammatory cells. These findings will help decipher the molecular mechanisms governing the functional consequences of EVs in the infarcted heart in order to design new therapeutic tools for treating cardiac ischemic diseases in the context of diabetes.

尽管采取了最先进的治疗方法，但心血管疾病（CVD）仍然是几乎所有欧洲国家的主要死亡原因。糖尿病是一个全球性的健康问题，估计全世界有 3.47 亿人受影响，预计未来十年发病率将增加 50%，使 CVD 风险增加约 3 倍。糖尿病治疗的一个显着失败是基于生活方式或药物的干预措施无法降低糖尿病引起的不良心室重构和心功能障碍的过高风险。因此，努力的方向是塑造心脏稳态的关键途径。心肌梗塞后，心脏组织释放多种可溶性趋化因子、细胞因子和生长因子，诱导炎症反应以塑造修复过程。然而，关于心肌如何启动局部修复过程或如何控制炎症反应，还有几个悬而未决的问题。此外，成纤维细胞诱导的纤维化也是心脏重塑的一个组成部分，并且缺乏关于缺血环境诱导的非许可机制的信息。我们的假设是，心肌梗死后，细胞外囊泡 (EV) 在心脏局部释放，其非编码 RNA 内容物的转移会影响局部炎症反应以及成纤维细胞依赖性活性和随后的修复机制。该提案旨在 1-表征和分析从 2 型糖尿病小鼠模型的梗死心肌中分离出的 EV 的非编码 RNA（microRNA 和长非编码 RNA）货物，这些 EV 来自培养的心肌细胞系和诱导多能细胞源心肌细胞，2-在糖尿病背景下识别和探索 EV 转移到体外和体内靶细胞的影响，并识别功能性运输非编码 RNA 到受体细胞的靶标， 3-通过使用合成脂质体递送有益的非编码RNA寡核苷酸或使用LNA/GapmeR抑制有害的特定非编码RNA来设计治疗方法，包括成纤维细胞和炎症细胞。该项目汇集了一名德国和两名法国合作伙伴，他们在心肌梗塞后炎症和纤维化以及细胞外囊泡和非编码 RNA 分析方面拥有领先的专业知识。他们的初步数据显示，心肌梗塞后在体外或体内产生的心肌细胞来源的细胞外囊泡中特异性非编码RNA包装，并且囊泡靶向受体成纤维细胞和炎症细胞。这些发现将有助于破译控制梗塞心脏中 EV 功能后果的分子机制，以便设计新的治疗工具来治疗糖尿病背景下的心脏缺血性疾病。

项目成果

Preclinical and Clinical Development of Noncoding RNA Therapeutics for Cardiovascular Disease

非编码RNA治疗心血管疾病的临床前和临床开发

• DOI: 10.1161/circresaha.119.315856
• 发表时间: 2020-02-27
• 期刊: Circulation Research
• 影响因子: 20.1
• 作者: Cheng;S. Kafert;T. Thum
• 通讯作者: T. Thum

RNA-based diagnostic and therapeutic strategies for cardiovascular disease

基于RNA的心血管疾病诊断和治疗策略

• DOI: 10.1038/s41569-019-0218-x
• 发表时间: 2019-06-11
• 期刊: Nature Reviews Cardiology
• 影响因子: 49.6
• 作者: Dongchao Lu;T. Thum
• 通讯作者: T. Thum

Long Noncoding RNA-Enriched Vesicles Secreted by Hypoxic Cardiomyocytes Drive Cardiac Fibrosis

缺氧心肌细胞分泌的富含非编码RNA的长囊泡驱动心脏纤维化

• DOI: 10.1016/j.omtn.2019.09.003
• 发表时间: 2019-09-13
• 期刊: Molecular Therapy. Nucleic Acids
• 作者: Franziska Kenneweg;C. Bang;K. Xiao;C. Boulanger;X. Loyer;S. Mazlan;B. Schroen;Steffie Hermans;A. Foinquinos;M. Hirt;T. Eschenhagen;S. Funcke;Stevan D Stojanović;Celina Genschel;K. Schimmel;A. Just;A. Pfanne;K. Scherf;Susann Dehmel;Stella M. Raemon;J. Fiedler;T. Thum
• 通讯作者: T. Thum