MicroRNAs, cardiac development and function

描述（由申请人提供）：MicroRNAs，心脏发育和功能MicroRNAs （miRNAs）是在大多数生物体中发现的一类小调控RNA分子。新出现的证据表明，miRNAs主要通过降解靶信使rna （mrna）和/或抑制蛋白质编码mrna的翻译，在多种生物过程中发挥重要的调节作用，包括细胞增殖、分化和生存。mirna也与许多人类疾病有关，包括心血管疾病。mirna的发现及其调控基因表达的潜在生物学功能为研究mirna如何参与“经典”基因表达通路开辟了一个全新的领域。迄今为止，已经在人类中发现了1000多种mirna；然而，大多数mirna的分子机制和体内功能尚不清楚。我们发现miR-208a通过调节关键同源盒转录因子Hop和应激性热休克蛋白70 （Hsp70）的表达水平，在一定程度上调节心脏肥厚生长。我们还发现心脏特异性RNA解旋酶Csm参与miRNA功能通路。斑马鱼Csm的破坏由于心肌细胞增殖的抑制而损害心脏形态发生。相反，Csm在小鼠心脏中的转基因过表达导致心脏增生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。本提案的总体目标是确定mirna在心脏中的生物学功能和分子机制。我们的中心假设是，mirna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，根据我们的初步观察，我们将验证我们的假设，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通过调节心肌细胞的miRNA稳态来调节其增殖。我们提出三个综合目标来检验我们的假设：目标#1。研究心脏特异性miR-208a在心脏中的体内功能及该miRNA调控的分子通路。目标# 2。目的：探讨心脏特异性RNA解旋酶Csm在miRNA通路中介导的分子事件。目标# 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. PUBLIC HEALTH RELEVANCE: MicroRNAs, cardiac development and function relevance congenital heart disease represents one of the most common classes of birth defects in humans. Cardiovascular disease is the leading cause of death in United States. Our studies will provide important insights into the molecular mechanisms by which miRNAs control mammalian heart development and cardiac gene expression. The molecular strategies we uncover in these studies will help define the ontogenesis of human congenital heart defects (CHD) with potential broader implications for understanding the pathophysiology of cardiac disease and failure in humans.