Role of miR25 in Heart Failure

miR25 在心力衰竭中的作用

• 批准号: 9249966
• 负责人: Roger J. Hajjar
• 金额: $ 64.1万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249966
• 关键词: Adult; Animal Model; Animals; Calcium; Calcium ion; Cardiac; Cardiac Myocytes; Cells; Clinical; Data; Development; Disease; Dose; Experimental Models; Gene therapy trial; Goals; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; In Vitro; Informatics; Injectable; International; Knockout Mice; Libraries; Link; Measurement; Measures; Messenger RNA; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; Pathway interactions; Patients; Phase III Clinical Trials; Phenotype; Physiological; Placebos; Proteins; Proteomics; Pump; Randomized; Role; SERCA2a; Sarcoplasmic Reticulum; Specificity; Structure; System; Systolic heart failure; Therapeutic; Tissues; Translational Repression; Transplantation; United States; Untranslated RNA; conventional therapy; design; gene therapy; hemodynamics; improved; in vivo; man; mimetics; mortality; mouse model; novel therapeutic intervention; novel therapeutics; prevent; protein expression; public health relevance; response; restoration; sarcoplasmic reticulum calcium ATPase; therapeutic target; transcriptome sequencing; vector

 DESCRIPTION (provided by applicant): Heart failure (HF) is a major cause of morbidity and mortality in the United States. While progress in conventional treatments is making steady and incremental gains, there is a critical need to explore new therapeutic approaches. Over the last five years, there has been a tremendous amount of information about microRNAs (miRs) in cardiac diseases. These small noncoding RNAs regulate protein expression by destabilization and/or translational inhibition of target messenger RNAs (mRNAs). Expression of miRs is abnormally regulated in cardiac hypertrophy and heart failure. In fact, miR expression seems to be more sensitive than mRNA to changes in clinical cardiac function. Single miRs tend to regulate numerous effectors within the same functional pathway, producing a coherent physiological response. Targeting miRs can therefore produce beneficial responses in disease states. Stable miR mimetics (agomiRs) and antagonists (antagomiRs) for specific miRs have been developed to prevent or reverse various diseases including experimental heart failure. Recently, our group found that miR25 is a key microRNA that regulates the cardiac sarcoplasmic reticulum calcium ATPase pump, SERCA2a. We showed antimiR25 treatment enhanced cardiac contractility and function through SERCA2a restoration in murine heart failure models. These early results suggest that inhibition of miR25 expression may be a promising therapeutic approach to enhance cardiac function in HF. Our overall hypothesis is that there are optimized sequences and functional structures of miR25 decoys. These decoys efficiently inhibit miR25 activity and consequently improve SERCA2a expression in cardiac myocytes of HF patients.

 描述（由申请人提供）：心力衰竭（HF）是美国发病率和死亡率的主要原因。虽然常规治疗的进展正在取得稳步和渐进的进展，但迫切需要探索新的治疗方法。在过去的五年中，有大量关于心脏疾病中microRNAs（miRs）的信息。这些小的非编码RNA通过靶信使RNA（mRNA）的去稳定化和/或翻译抑制来调节蛋白质表达。miR的表达在心肌肥厚和心力衰竭中受到异常调节。事实上，miR表达似乎比mRNA对临床心脏功能的变化更敏感。单个miR倾向于调节同一功能途径内的众多效应物，产生连贯的生理反应。因此，靶向miR可以在疾病状态下产生有益的反应。已经开发了针对特定miR的稳定miR模拟物（agomiR）和拮抗剂（agomiR）以预防或逆转各种疾病，包括实验性心力衰竭。 最近，我们的研究小组发现miR 25是调节心肌肌浆网钙ATP酶泵SERCA 2a的关键microRNA。我们显示，在鼠心力衰竭模型中，抗miR 25治疗通过SERCA 2a恢复增强心脏收缩力和功能。这些早期结果表明，抑制miR 25表达可能是一种有前途的治疗方法，以提高心脏功能的HF。我们的总体假设是存在miR 25诱饵的优化序列和功能结构。这些诱饵有效地抑制miR 25活性，从而改善HF患者心肌细胞中的SERCA 2a表达。