Role of miR25 in Heart Failure

miR25 在心力衰竭中的作用

• 批准号: 8914275
• 负责人: Roger J. Hajjar
• 金额: $ 64.53万
• 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/8914275
• 关键词: Adult; Animal Model; 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; International; 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; novel therapeutic intervention; 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) 是美国发病和死亡的主要原因。虽然传统治疗正在取得稳定和渐进的进展，但迫切需要探索新的治疗方法。在过去的五年里，出现了大量关于 microRNA (miR) 在心脏病中的作用的信息。这些小非编码 RNA 通过靶信使 RNA (mRNA) 的不稳定和/或翻译抑制来调节蛋白质表达。 miRs 的表达在心脏肥大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器，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。稳定的 miR 模拟物 (agomiR) 和特定 miR 的拮抗剂 (antagomiR) 已被开发用于预防或逆转包括实验性心力衰竭在内的各种疾病。 最近，我们课题组发现miR25是调节心脏肌浆网钙ATP酶泵SERCA2a的关键microRNA。我们发现 antimiR25 治疗通过小鼠心力衰竭模型中 SERCA2a 的恢复增强了心肌收缩力和功能。这些早期结果表明，抑制 miR25 表达可能是增强心力衰竭心脏功能的一种有前景的治疗方法。我们的总体假设是 miR25 诱饵存在优化的序列和功能结构。这些诱饵有效抑制 miR25 活性，从而改善心力衰竭患者心肌细胞中 SERCA2a 的表达。