MicroRNA Control of Cardiac Gene Expression, Function and Disease

描述（由申请人提供）：微小RNA（miRNAs）通过抑制靶mRNA的翻译或促进其降解而作为基因表达的负调节因子。我们小组和其他人最近的研究揭示了miRNAs在控制心脏功能的各个方面中的深刻和意想不到的作用，包括控制肌细胞生长，心室壁的完整性，收缩性，基因表达和维持心律，为心脏病提供了未发现的调节机制和潜在的治疗靶点。特定的miRNAs在患病的心脏中错误表达，并且在小鼠中进行的功能获得和丧失实验表明这些miRNAs对于多种形式的心脏病是必要的和足够的。特别令人着迷的是发现了一个密切相关的miRNA家族，它们由肌球蛋白重链基因的内含子编码。在心脏中，这些miRNA控制肌球蛋白表达、应激依赖性生长和纤维化、甲状腺激素反应性，并抑制快速骨骼肌基因表达。在骨骼肌中，这些miRNAs的一个子集调节快肌纤维与慢肌纤维的特性。我们将这些miRNAs和它们嵌入其中的肌球蛋白基因称为Myo-miR网络。Myo-miR网络在进化上是保守的，受上游信号通路的调节，并通过刚刚开始被揭示的机制来调节下游靶点。该项目的总体目标是确定Myo-miR网络调节心脏和骨骼肌功能、发育和疾病的分子机制。最终，我们希望利用我们对miRNA生物学的理解来揭示肌肉疾病的新疾病机制和治疗方法。公共卫生相关性：该项目的目标是探索心脏中压力调节microRNA的作用机制，并最终利用我们对microRNA生物学的理解来揭示心脏病的新疾病机制和治疗方法。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The goal of this project is to explore the mechanisms of action of stress-regulated microRNAs in the heart and, ultimately, to use our understanding of microRNA biology to uncover new disease mechanisms and therapeutic approaches for heart disease.