MicroRNAs, cardiac development and function

MicroRNA、心脏发育和功能

• 批准号: 8394573
• 负责人: Da-Zhi Wang
• 金额: $ 41.41万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-16 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394573
• 关键词: Binding; Biogenesis; Biological Process; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Proliferation; Code; Congenital Abnormality; Congenital Heart Defects; Cytoplasmic Granules; Data; Development; Dilated Cardiomyopathy; Elements; Event; Functional disorder; Gene Expression; Goals; Growth; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Heat-Shock Proteins 70; Homeobox; Homeostasis; Human; Humulus; Hyperplasia; Knockout Mice; Mediating; Messenger RNA; MicroRNAs; Molecular; Morphogenesis; Mus; Myocardium; Organism; Pathway interactions; Play; Process; Proteins; RNA; RNA Helicase; Role; Site; Stress; Striated Muscles; Testing; Transgenic Mice; Transgenic Organisms; Translational Repression; Translations; United States; Zebrafish; base; biological adaptation to stress; cardiogenesis; congenital heart disorder; functional loss; heart function; human DICER1 protein; human disease; in vivo; insight; loss of function; mouse model; overexpression; response; transcription factor

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.

描述（由申请人提供）：MicroRNA、心脏发育和功能MicroRNA（miRNAs）是在大多数生物体中发现的一类小的调节RNA分子。越来越多的证据表明，miRNAs主要通过降解靶信使RNA（mRNAs）和/或抑制蛋白质编码mRNAs的翻译，在细胞增殖、分化和存活等多种生物学过程中发挥重要的调控作用。miRNAs也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潜在的生物学功能为研究miRNAs如何参与“经典”基因表达途径开辟了一个全新的领域。迄今为止，已经在人类中鉴定了超过1，000种miRNA;然而，大多数miRNA的分子机制和体内功能仍然未知。 我们发现miR-208 a部分通过调节关键同源框转录因子Hop和应激反应性热休克蛋白70（Hsp 70）的表达水平来调节心脏肥大性生长。我们还发现心脏特异性RNA解旋酶Csm参与miRNA功能途径。由于心肌细胞增殖受到抑制，斑马鱼中Csm的破坏会损害心脏形态发生。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在多种脊椎动物物种中的重要作用。 该提案的总体目标是确定心脏中miRNAs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回路的组成部分。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-208 a调节Hop和Hsp 70的表达水平以传递心肌细胞中的应激反应。我们进一步假设，Csm介导心肌细胞中的miRNA稳态，以调节其增殖。我们提出了三个综合目标来测试我们的假设：目标#1。研究心脏特异性miR-208 a在心脏中的体内功能及其调控的分子通路。目标2。研究心肌特异性RNA解旋酶Csm在miRNA通路中介导的分子事件。目标3。目的：明确CSM在心脏发育和心肌细胞增殖中的作用。