Regulation of cardiac hypertrophy by microRNA-21

描述（由申请人提供）：肥厚性心脏病在美国影响数百万人，总医疗费用估计在数十亿美元。为了预防和治疗这种疾病，研究驱动心脏肥厚和重塑的机制是必要的。该项目的长期目标是确定驱动这一病理过程的分子机制，并提出治疗心脏肥厚的新靶点。MicroRNAs （miRs）与心脏发育和疾病密切相关。MiRs是一种小RNA分子，通过诱导序列特异性mRNA的翻译沉默或降解来降低靶基因的表达。具体来说，miR-21被确定为压力过载肥厚后上调最多的miR。过表达miR-21诱导心肌肥厚。这些数据强烈提示miR-21在应激诱导的心脏肥大和重构中发挥作用。本项目将研究miR-21在心肌肥厚中的作用。这将通过研究miR-21的应激反应增强剂来实现。这种增强子的特性将提示调节miR-21表达的机制，从而暗示miR-21药理学调节的可能机制。miR-21在心脏肥厚中的作用将通过产生miR-21条件敲除小鼠在体内进行检验。miR-21的整体缺失和心脏特异性缺失都将允许解剖miR在应激诱导的肥大和重塑中的作用。miR-21诱导心肌肥厚的机制将被确定。miR-21靶基因的测定将提示驱动心肌肥厚的新分子机制。这些研究将为心脏疾病的调节机制提供深入的见解，并将为未来治疗心脏肥厚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.