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

基本信息

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

项目摘要

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.

尽管最先进的治疗方法，但心血管疾病（CVD）几乎是几乎所有欧洲国家死亡的主要原因。糖尿病是全球健康问题，估计在全球有3.47亿人受影响的人，预计未来十年的发病率增加了50％，大约增加了CVD风险的3倍。糖尿病治疗的严重失败是生活方式或药物的干预措施无法影响糖尿病引起的不良心室重塑和心脏功能障碍的过量风险。因此，努力是针对塑造心脏稳态的关键途径。心肌梗塞后，心脏组织释放了几种可溶性趋化因子，细胞因子和生长因子，这些因子和生长因子诱导炎症反应以塑造修复过程。但是，关于心肌如何启动局部修复过程或如何操纵炎症反应有几个开放问题。另外，成纤维细胞诱导的纤维化也是心脏重塑的组成部分，缺乏缺血环境引起的非耐药机制的信息。我们的假设是，细胞外囊泡（EV）在心肌梗塞后在心脏中局部释放，并且其非编码RNA含量的转移会影响局部炎症反应以及依赖成纤维细胞依赖性活性并随后修复机制。 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在糖尿病背景下的体内，以及识别功能传输的非编码RNA的靶标，包括成纤维细胞和炎症细胞，使用合成脂质体或使用抑制性的非candna/decap rnna/decans rnna/dynaas/dynna/dyna/dnna/dnaas rna/dnna/dnaas rna/dnaas rna/dna rna/dnna/dnaas rna/dnaas/dnaas/dnaas conts 3-设计治疗方法。该项目汇集了一个德国和两个法国伙伴，在心肌梗塞以及细胞外囊泡和非编码RNA分析方面具有领先的炎症和纤维化专业知识。他们的初步数据表明，在心肌梗塞后在体外或体内产生的心肌细胞起源的特定非编码RNA包装以及靶向受体成纤维细胞和炎症细胞的囊泡。这些发现将有助于解读梗塞心脏中电动汽车功能后果的分子机制，以设计新的治疗工具，用于在糖尿病的背景下治疗心脏缺血性疾病。