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（由适用提供）：心力衰竭（HF）是美国发病率和死亡率的主要原因。尽管常规治疗的进展正在稳定和逐步增长，但探索新的治疗方法的迫切需要。在过去的五年中，有关心脏疾病中的microRNA（miR）的信息很多。这些小的非编码RNA通过对靶标的RNA（mRNA）的不稳定和/或翻译抑制来调节蛋白质表达。 miR的表达在心脏肥大和心力衰竭中受到异常调节。实际上，miR表达似乎比mRNA更敏感，对改变临床心脏功能的变化。单个miR倾向于在同一功能途径中调节众多效应，从而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。已经开发出用于预防或逆转各种疾病，包括实验性心力衰竭的稳定的miR mimetics（Agomirs）和拮抗剂（Antagomirs）。 最近，我们的小组发现MiR25是调节心脏肌浆网钙ATPase Pump，SERCA2A的关键microRNA。我们通过鼠心力衰竭模型中的SERCA2A恢复显示了Antimir25治疗增强的心脏收缩性和功能。这些早期结果表明，抑制miR25表达可能是增强HF心脏功能的有前途的治疗方法。我们的总体假设是MiR25诱饵有优化的序列和功能结构。这些诱饵有效地抑制了miR25活性，因此改善了HF患者心肌细胞的SERCA2A表达。