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

心血管疾病（CVD）是几乎所有欧洲国家死亡的主要原因，尽管有最先进的治疗方法。糖尿病是一个全球性的健康问题，全世界估计有3.47亿人受其影响，预计未来十年发病率将增加50%，使心血管疾病的风险增加约3倍。以生活方式或药物为基础的干预措施无法影响糖尿病引起的不良心室重构和心功能障碍的过度风险，这是糖尿病治疗中一个显著的失败。因此，努力的方向是塑造心脏稳态的关键途径。心肌梗死后，心脏组织释放几种可溶性趋化因子、细胞因子和生长因子，诱导炎症反应，形成修复过程。然而，关于心肌如何启动局部修复过程或如何操纵炎症反应，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构的一个组成部分，缺乏关于缺血环境诱导的非允许机制的信息。我们的假设是，心肌梗死后，细胞外囊泡（EVs）在心脏局部释放，其非编码RNA含量的转移影响局部炎症反应、成纤维细胞依赖性活性和随后的修复机制。本课题旨在：1 .从2型糖尿病小鼠模型梗死心肌中分离EV的非编码RNA （microRNAs和长链非编码RNA）的特征和分析，从培养的心肌细胞细胞系和诱导的多能细胞来源的心肌细胞中分离EV的非编码RNA， 2 .在糖尿病背景下，鉴定和探索EV向靶细胞转移的体外和体内影响，并确定功能性转运的非编码RNA到受体细胞的靶标。包括成纤维细胞和炎症细胞，3 .设计治疗方法，要么使用合成脂质体传递有益的非编码RNA寡核苷酸，要么使用LNA/GapmeRs抑制有害的特异性非编码RNA。该项目汇集了一家德国和两家法国合作伙伴，他们在心肌梗死后的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，特定的非编码RNA被包装到心肌细胞起源的细胞外囊泡中，无论是在体外还是在体内，这些囊泡都是在心肌梗死后产生的，并且囊泡靶向成纤维细胞和炎症细胞。这些发现将有助于破译EVs在梗死心脏中功能后果的分子机制，从而设计治疗糖尿病背景下心脏缺血性疾病的新治疗工具。

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.