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.

心血管疾病是美国的首要死因。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 (miRNA) 是大多数生物体中发现的一类小调节 RNA 分子。 新的证据表明 miRNA 发挥着重要的调节作用，主要是通过 降解目标信使 RNA (mRNA) 和/或抑制蛋白质编码的翻译 多种生物过程中的 mRNA，包括细胞增殖、分化和 生存。 miRNA 还与许多人类疾病有关，包括心血管疾病 疾病。 miRNA的发现及其调控基因的潜在生物学功能 表达开辟了研究 miRNA 如何参与“经典”的全新领域 基因表达途径。迄今为止，已在人类中鉴定出 2,000 多种 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明确生物学功能和分子机制 心脏中的 miRNA。我们的中心假设是 miRNA 是 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-208a 通路调节心脏功能是 上下文相关的方式。我们提出三个综合目标来检验我们的假设： 目标#1。病理生理应激下 Trbp 在心脏中的功能是什么？ 目标#2。 miRNA 通路中 Trbp 功能的特异性如何定义 心？ 目标#3。 miR-208a 在心脏中的作用是什么？它是如何发挥作用的？ 我们的研究将为 miRNA 的分子机制提供重要的见解。 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本体发生 对于理解心脏病的病理生理学具有潜在更广泛的影响 人类。