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（miRNA）是大多数生物体中发现的一类小调节RNA分子。新兴的证据已经确定，miRNA在多种生物学过程中，主要是通过降解靶标MESENGERNA（mRNA）和/或抑制蛋白质编码mRNA的翻译（包括细胞增殖，分化和生存）中的蛋白质编码mRNA的翻译。在包括心血管疾病在内的许多人类疾病中也暗示了miRNA。 miRNA的发现及其在调节基因表达的潜在生物学功能开辟了一个全新的领域，以研究miRNA如何参与“经典”基因表达途径。迄今为止，在人类中已经确定了1,000多个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-208a通过调节关键同源转录因子Hop和应力负责热激蛋白70（HSP70）的表达水平（HSP70）来调节心脏肥厚性生长。我们还表明，心脏特异性RNA解旋酶CSM参与miRNA功能途径。由于心肌细胞增殖的抑制，斑马鱼中CSM的破坏会损害心脏形态发生。相反，CSM在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，从而证实了CSM在多种脊椎动物中的重要作用。 该建议的总体目标是定义心脏中miRNA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，我们将测试MiR-208a调节HOP和HSP70的表达水平以传达心肌细​​胞中的胁迫反应的假设。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的旨在检验我们的假设：目标＃1。研究心脏中心脏特异性miR-208a的体内功能以及该miRNA调节的分子途径。目标＃2。为了研究miRNA途径中CSM（一种心脏特异性RNA解旋酶）介导的分子事件。目标＃3。定义CSM在心脏发育和心肌细胞增殖中的作用。