MicroRNAs, cardiac function and cardiomyopathy

MicroRNA、心脏功能和心肌病

• 批准号: 9394282
• 负责人: Da-Zhi Wang
• 金额: $ 53.54万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9394282
• 关键词: Biological Process; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Cell Proliferation; Code; Congenital Abnormality; Congenital Heart Defects; Contractile Proteins; Data; Dilated Cardiomyopathy; Event; Functional disorder; Funding; Gene Expression; Genetic; Goals; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Human; Investigation; Knockout Mice; Messenger RNA; MicroRNAs; Molecular; Mus; Mutant Strains Mice; NCOA6 gene; Organism; PTEN gene; Pathologic; Pathway interactions; Play; Proteins; RNA; RNA-Binding Proteins; Regulation; Reporting; Role; SOX6 gene; Specificity; Stress; Testing; Translations; United States; Work; biological adaptation to stress; cardiac regeneration; cardiogenesis; congenital heart disorder; gene function; genome-wide analysis; human disease; in vivo; insight; loss of function; mouse model; mutant; overexpression; pressure; response; young adult

Cardiovascular disease is the leading cause of death in United States. However, the molecular events that control heart development and cardiac function are not fully understood. 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 by 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 implicated in many human diseases, including cardiovascular disease. The discovery of miRNAs and their potential biological functions in regulating gene expression opened a completely new field to investigate how miRNAs participate in “classical” gene expression pathways. To date, more than 2,000 miRNAs have been identified in humans; however, the molecular mechanisms and the in vivo functions of most miRNAs remain unknown. The overall goal of this study 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 cardiac gene expression and function. More specifically, we will test our hypothesis that the Trbp-miR-208a pathway regulates cardiac function is a context-dependent manner. We present three integrative aims to test our hypothesis: Aim #1. What is the function of Trbp in the heart under pathophysiological stresses? Aim #2. How is the specificity of Trbp function in the miRNA pathway defined in the heart? Aim #3. What is the role of miR-208a in the heart and how does it work? Our studies will provide important insights into the molecular mechanisms by which miRNAs control mammalian heart development, function and cardiac gene expression. The molecular strategies we uncover in these studies will help define the ontogenesis of heart failure with potential broader implications for understanding the pathophysiology of cardiac disease in humans.

心血管疾病是美国人死亡的主要原因。然而，分子 控制心脏发育和心脏功能的事件尚未完全了解。 microRNA（miRNAs）是一类存在于大多数生物体中的小的调控RNA分子。 新出现的证据已经确定，miRNAs发挥重要的调控作用，主要是通过 降解靶信使RNA（mRNA）和/或抑制蛋白质编码的翻译 mRNA在多种生物过程中，包括细胞增殖、分化和 生存miRNAs还与许多人类疾病有关，包括心血管疾病， 疾病miRNAs的发现及其在基因调控中的潜在生物学功能 表达开辟了一个全新的领域，研究miRNAs如何参与“经典” 基因表达途径到目前为止，已经在人类中鉴定出超过2,000种miRNA; 然而，大多数miRNA的分子机制和体内功能仍然存在， 未知 本研究的总体目标是确定生物学功能和分子机制 心脏中的miRNAs。我们的中心假设是，miRNAs是细胞内的组成部分， 控制心脏基因表达和功能的分子电路。更具体地说，我们 将检验我们的假设，即Trbp-miR-208 a通路调节心脏功能是一种 context-dependent方式。我们提出了三个综合目标来检验我们的假设： 目标1。Trbp在病理生理应激下心脏中的功能是什么？ 目标2。Trbp在miRNA通路中的功能特异性如何在 心脏？ 目标3。miR-208 a在心脏中的作用是什么，它是如何工作的？ 我们的研究将提供重要的见解的分子机制，通过微RNA 控制哺乳动物心脏发育、功能和心脏基因表达。分子 我们在这些研究中发现的策略将有助于定义心力衰竭的个体发生， 潜在的更广泛的意义，了解心脏病的病理生理学， 人类