MicroRNA Control of Cardiac Gene Expression, Function and Disease

项目摘要/摘要 MicroRNAs(MiRNAs)通过抑制翻译而作为基因表达的负调控因子 或促进靶基因mRNA的降解。我们小组和其他人最近的研究表明 揭示了miRNAs在控制心脏不同方面的深刻和意想不到的作用 功能，包括控制心肌细胞的生长，室壁的完整性，收缩， 基因表达和维持心律，提供了未知的一瞥 心脏病的调控机制和潜在的治疗靶点。特定的miRNAs是 在患病的心脏中错误表达，以及小鼠的获得和功能丧失实验表明 这些miRNA对于多种形式的心脏病来说是必要的和足够的。尤其是 引人入胜的是发现了一个密切相关的miRNAs家族，这些miRNAs由 肌球蛋白重链基因。在心脏，这些miRNAs控制着肌球蛋白的表达、压力 依赖性生长和纤维化、甲状腺激素反应性和抑制快速骨骼肌 基因表达。在骨骼肌中，这些miRNAs的一个子集调节快慢 肌纤维身份。我们指的是这些miRNAs及其嵌入的肌球蛋白基因， 作为Myo-MIR网络。Myo-miR网络在进化上是保守的，受到调控 通过上游信号通路并通过以下机制调节下游靶点 才刚刚开始揭开面纱。这个项目的总体目标是定义分子 Myo-miR网络调节心肌和骨骼肌功能的机制， 发展和疾病。最终，我们希望利用我们对miRNA生物学的理解来 发现肌肉疾病的新发病机制和治疗方法。

Project Summary/Abstract microRNAs (miRNAs) act as negative regulators of gene expression by inhibiting the translation or promoting the degradation of target mRNAs. Recent studies by our group and others have revealed profound and unexpected roles for miRNAs in the control of diverse aspects of cardiac function, including the control of myocyte growth, integrity of the ventricular wall, contractility, gene expression, and maintenance of cardiac rhythm, providing glimpses of undiscovered regulatory mechanisms and potential therapeutic targets for heart disease. Specific miRNAs are mis-expressed in diseased hearts, and gain and loss-of-function experiments in mice have shown these miRNAs to be necessary and sufficient for multiple forms of heart disease. Particularly fascinating is the discovery of a family of closely related miRNAs that are encoded by introns of myosin heavy chain genes. In the heart, these miRNAs control myosin expression, stress dependent growth and fibrosis, thyroid hormone responsiveness, and repress fast skeletal muscle gene expression. In skeletal muscle, a subset of these miRNAs regulates fast versus slow myofiber identity. We refer to these miRNAs and the myosin genes in which they are embedded, as the Myo-miR network. The Myo-miR network, which is evolutionarily conserved, is regulated by upstream signaling pathways and modulates downstream targets through mechanisms that are only beginning to be unveiled. The overall goal of this project is to define the molecular mechanisms whereby the Myo-miR network modulates cardiac and skeletal muscle function, development and disease. Ultimately, we hope to exploit our understanding of miRNA biology to uncover new disease mechanisms and therapeutic approaches for muscle disease.