Regulation of cardiac hypertrophy by microRNA-21

描述（由申请人提供）：肥厚性心脏病影响美国数百万人，总医疗费用估计为数十亿美元。为了预防和治疗这种疾病，有必要研究驱动心脏肥大和重塑的机制。该项目的长期目标是确定驱动这一病理过程的分子机制，并提出治疗心脏肥大的新靶点。microRNAs（miRs）与心脏发育和疾病密切相关。miR是通过诱导序列特异性mRNA翻译沉默或降解来降低靶基因表达的小RNA分子。具体而言，miR-21被鉴定为压力超负荷肥大后上调最多的miR。miR-21过表达诱导心肌肥大。这些数据有力地表明，miR-21在应激诱导的心脏肥大和重塑中起作用。本项目将研究miR-21在心肌肥大中的作用。这将通过研究miR-21的应激响应增强子来进行。该增强子的表征将提示调节miR-21表达的机制，从而暗示药理学miR-21调节的可能机制。将通过产生miR-21条件性敲除小鼠在体内检查miR-21在心脏肥大中的作用。miR-21的整体和心脏特异性缺失将允许解剖该miR在应激诱导的肥大和重塑中的作用。将确定miR-21诱导心脏肥大的机制。miR-21靶基因的确定将提示驱动心脏肥大的新分子机制。这些研究将提供对调节心脏疾病的机制的深入了解，并将为未来治疗心脏肥大确定潜在的治疗靶点。

DESCRIPTION (provided by applicant): Hypertrophic cardiac disease affects millions of people in the United States with total health care costs estimated in the billions of dollars. Investigation of the mechanisms that drive cardiac hypertrophy and remodeling are necessary in order to prevent and treat this disease. The long term goals of this project are to identify molecular mechanisms that drive this pathologic process, and to suggest new targets for the treatment of cardiac hypertrophy. MicroRNAs (miRs) have beeri strongly implicated in both heart development and disease. MiRs are small RNA molecules that decrease the expression of target genes by inducing sequence specific mRNA translational silencing or degradation. Specifically, miR-21 was identified as the most upregulated miR after pressure overload hypertrophy. Overexpression of miR-21 induces cardiac hypertrophy. These data strongly suggest that miR-21 plays a role in stress-induced cardiac hypertrophy and remodeling. This project will study the role of miR-21 in cardiac hypertrophy. This will be performed by investigation of the stress-responsive enhancer of miR-21. Characterization of this enhancer will suggest mechanisms that regulate the expression of miR-21 and thus implicate possible mechanisms of pharmacologic miR-21 modulation. The role of miR-21 in cardiac hypertrophy will be examined in vivo by generation of a miR-21 conditional knockout mouse. Both global and cardiac-specific deletion of miR-21 will allow for dissection of the role of this miR in stress-induced hypertrophy and remodeling. The mechanism of miR-21 induced cardiac hypertrophy will be determined. Determination of miR-21 target genes will suggest novel molecular mechanisms driving cardiac hypertrophy. These studies will provide insight into the mechanisms regulating cardiac disease, and they will define potential therapeutic targets for the future treatment of cardiac hypertrophy.