Role of the long intergenic non-coding (linc) RNA NRON in cardiac disease

哺乳动物的基因组由许多转录中心组成，这些转录中心被一长段基因间空间分隔开，由于我们的理解有限，这些空间也被称为基因组的暗物质。长的非编码RNA（lincRNA）位于这些基因间延伸内并在其中转录，最近的证据表明其中一些序列在很大程度上参与基因调控。然而，lincRNA在心脏疾病中的作用迄今为止从未被探索过。 我们的初步结果表明，心脏肥大物质抑制心肌细胞lincRNA NRON（NFAT的非编码调节因子）的表达。此外，我们发现NRON表达在不同的心脏疾病模型（心肌梗死和横主动脉缩窄）中受损，并且培养的心肌细胞中的NRON沉默导致肥大。在本资助申请中，我们建议对lincRNA NRON在心脏疾病中的作用进行深入分析。为此，我们将采用NRON基因缺失的动物模型来研究这些动物是否更容易患心脏病。接下来，我们将测试腺病毒介导的基因治疗恢复NRON表达是否对心脏功能有任何有益的影响，基于我们有前途的体外结果。这项研究将首次强调lincRNA在心脏疾病中的作用，并可能为心脏疾病的新治疗方式开辟机会。

The mammalian genome consists of numerous -foci- of transcription that are separated by long stretches of intergenic space, also entitled -the dark matter of the genome- because of our limited understanding. Long non-coding RNAs (lincRNAs) are located and transcribed within these intergenic stretches, and recent evidence suggest some of those sequences to be largely involved in gene regulation. However, the role of lincRNAs in cardiac diseases has never been explored so far. Our preliminary results show that cardiac hypertrophic substances suppress cardiomyocyte expression of the lincRNA NRON (Non-coding Regulator of NFAT). Further, we found NRON expression to be impaired in different cardiac disease models (myocardial infarction and transverse aortic constriction) and NRON silencing in cultured cardiomyocytes resulted in hypertrophy. In the present grant application, we propose to perform an in depth analysis of the role of the lincRNA NRON in cardiac diseases. For this purpose, we will employ animal models with genetic deletion of NRON to study if these animals are more prone to cardiac disease. Next, we will test if adenoviral mediated gene therapy to restore NRON expression has any beneficial effects on cardiac function based on our promising in vitro results. This study will be the first to highlight the role of a lincRNA in cardiac diseases and may open-up opportunities for new therapeutic modalities for cardiac diseases.