MicroRNAs, cardiac development and function

描述(申请人提供)：microRNAs，心脏发育和功能microRNAs(MiRNAs)是一类存在于大多数生物体中的小调节RNA分子。越来越多的证据表明，miRNAs在多种生物学过程中发挥着重要的调节作用，主要是通过降解靶信使RNAs和/或抑制编码蛋白质的mRNAs的翻译，包括细胞的增殖、分化和存活。MiRNAs还与许多人类疾病有关，包括心血管疾病。MiRNAs的发现及其在基因表达调控中的潜在生物学功能为研究miRNAs如何参与经典的基因表达途径开辟了一个全新的领域。到目前为止，已在人类中发现了1000多个miRNAs；然而，大多数miRNAs的分子机制和体内功能仍不清楚。我们发现miR-208A通过调节关键的同源盒转录因子Hop和应激反应热休克蛋白70(Hsp70)的表达水平来调节心肌肥大生长。我们还发现心脏特异的RNA解旋酶CSM参与miRNA功能通路。斑马鱼中CSM的破坏通过抑制心肌细胞的增殖而损害心脏形态发生。相反，转基因CSM在小鼠心脏中的过表达导致心肌细胞过度增殖和心肌细胞过度增殖，证实了CSM在多种脊椎动物中的重要作用。这项提议的总体目标是定义心脏中miRNAs的生物学功能和分子机制。我们的中心假设是miRNAs是控制哺乳动物心血管发育和功能的分子电路的组成部分。更具体地说，基于我们的初步观察，我们将检验我们的假设，即miR-208A调节Hop和Hsp70的表达水平，以传递心肌细胞的应激反应。我们进一步假设，CSM介导心肌细胞miRNA的动态平衡，以调节其增殖。我们提出了三个综合目标来验证我们的假设：目的1.研究心脏特异性miR-208A在心脏中的体内功能及其调控的分子途径。目的#2.研究心肌特异的RNA解旋酶CSM在miRNA途径中的分子事件。目的#3.明确CSM在心脏发育和心肌细胞增殖中的作用。

DESCRIPTION (provided by applicant): MicroRNAs, cardiac development and function MicroRNAs (miRNAs) are a class of small regulatory RNA molecules found in most organisms. Emerging evidence has established that miRNAs play important regulatory roles, mainly through degrading target messenger RNAs (mRNAs) and/or inhibiting translation of protein-coding mRNAs in a variety of biological processes, including cell proliferation, differentiation and survival. miRNAs are also implied in many human diseases, including cardiovascular disease. The discovery of miRNAs and their potential biological function in regulating gene expression opened a completely new field to investigate how miRNAs participate in "classical" gene expression pathways. To date, more than 1,000 miRNAs have been identified in humans; however, the molecular mechanisms and the in vivo functions of most miRNAs remain unknown. We found that miR-208a regulates cardiac hypertrophic growth, in part, by modulating the expression level of the key homeobox transcription factor Hop and stress responsible heat shock protein 70 (Hsp70). We also showed that a cardiac-specific RNA helicase Csm participates in miRNA functional pathways. Disruption of Csm in zebrafish impairs cardiac morphogenesis owing to a suppression of cardiomyocyte proliferation. Conversely, transgenic overexpression of Csm in murine hearts led to cardiac hyperplasia and cardiomyocyte overproliferation, confirming the essential role of Csm in multiple vertebrate species. The overall goal of this proposal is to define the biological function and the molecular mechanisms of miRNAs in the heart. Our central hypothesis is that miRNAs are components of the molecular circuitry that controls mammalian cardiovascular development and function. More specifically, based on our preliminary observations, we will test our hypothesis that miR-208a regulates the expression level of Hop and Hsp70 to convey stress response in cardiomyocytes. We further hypothesize that Csm mediates miRNA homeostasis in cardiomyocytes to regulate their proliferation. We present three integrative aims to test our hypothesis: Aim #1. To study the in vivo function of cardiac-specific miR-208a in the heart and the molecular pathways regulated by this miRNA. Aim #2. To investigate the molecular events mediated by Csm, a cardiac-specific RNA helicase, in miRNA pathway. Aim #3. To define the role of Csm in cardiac development and cardiomyocyte proliferation.