Role of miR25 in Heart Failure

 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稳步和渐进地取得进展，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的microRNAs(MiRs)的信息。这些小的非编码RNA通过不稳定和/或翻译抑制靶信使RNA(MRNAs)来调节蛋白质的表达。在心肌肥厚和心力衰竭中，miRs的表达被异常调节。事实上，miR的表达似乎比mRNA对临床心功能的变化更敏感。单个MIR往往调节同一功能通路中的许多效应器，产生一致的生理反应。因此，靶向miRs可以在疾病状态下产生有益的反应。针对特定miR的稳定miR模拟物(AgomiRs)和拮抗剂(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，我们的团队发现miR25是一个关键的microRNA，它调节心肌肌浆网钙ATPase泵SERCA2a。我们发现，在小鼠心力衰竭模型中，抗iR25治疗通过SERCA2a恢复增强了心脏的收缩能力和功能。这些早期结果表明，抑制miR25的表达可能是一种有前途的治疗方法，可以增强心功能。我们的总体假设是miR25诱饵存在优化的序列和功能结构。这些诱骗有效地抑制了miR25的活性，从而提高了心衰患者心肌细胞中SERCA2a的表达。

 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.