Role of miR25 in Heart Failure

miR25 在心力衰竭中的作用

基本信息

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
项目类别：
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

项目摘要

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。虽然传统治疗方法正在取得稳定和渐进的进展，但目前迫切需要探索新的治疗方法。过去五年，有大量关于心脏病中的 microRNA (miR) 的信息，这些小非编码 RNA 通过破坏靶信使 RNA (mRNA) 的表达稳定和/或翻译抑制来调节蛋白质表达。 miR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。因此，miR 可以在疾病状态下产生有益的反应，已开发出稳定的 miR 模拟物 (agomiR) 和特定 miR 的拮抗剂 (antagomiR)，以预防或逆转包括实验性心力衰竭在内的各种疾病。最近，我们的小组发现 miR25 是调节心脏肌浆网钙 ATP 酶泵 SERCA2a 的关键 microRNA。我们在小鼠心力衰竭模型中表明，抗 miR25 治疗可通过恢复 SERCA2a 增强心肌收缩力和功能。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途的治疗方法，我们的总体假设是 miR25 诱饵存在优化的序列和功能结构。诱饵有效抑制 miR25 活性，从而提高心力衰竭患者心肌细胞中 SERCA2a 的表达。