Regulation of cardiac hypertrophy by microRNA-21

microRNA-21 对心脏肥大的调节

• 批准号: 7754005
• 负责人: David Patrick
• 金额: $ 2.8万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-18 至 2012-12-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7754005
• 关键词: 3' Untranslated Regions; Affect; Animal Model; Automobile Driving; Cardiac; Cardiomyopathies; Data; Disease; Dissection; Enhancers; Future; Gene Expression; Gene Targeting; Generations; Goals; Health Care Costs; Heart Diseases; Heart Hypertrophy; Heart failure; Human; Hypertrophy; Investigation; Knockout Mice; Messenger RNA; MicroRNAs; Molecular; Pathologic; Pathologic Processes; Pattern; Play; Process; Regulation; Regulator Genes; Role; Small RNA; Stress; Translations; United States; Up-Regulation; cardiogenesis; in vivo; insight; loss of function; mRNA Transcript Degradation; mouse model; novel; overexpression; pressure; prevent; response; therapeutic target

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.

描述（由申请人提供）：肥厚性心脏病影响着美国数百万人，医疗保健总费用估计达数十亿美元。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。 MicroRNA (miR) 与心脏发育和疾病密切相关。 MiR 是小 RNA 分子，可通过诱导序列特异性 mRNA 翻译沉默或降解来降低靶基因的表达。具体而言，miR-21 被确定为压力超负荷肥大后上调最多的 miR。 miR-21 的过度表达会诱导心脏肥大。这些数据强烈表明 miR-21 在应激诱导的心脏肥大和重塑中发挥作用。该项目将研究 miR-21 在心脏肥大中的作用。这将通过研究 miR-21 的应激反应增强子来完成。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。将通过生成 miR-21 条件敲除小鼠来体内检查 miR-21 在心脏肥大中的作用。 miR-21 的整体和心脏特异性删除将允许剖析该 miR 在应激诱导的肥大和重塑中的作用。 miR-21诱导心脏肥大的机制将被确定。 miR-21 靶基因的确定将揭示驱动心脏肥大的新分子机制。这些研究将深入了解调节心脏病的机制，并将确定未来治疗心脏肥大的潜在治疗靶点。