Micro-RNA regulation of the cardiac exercise response

描述（由申请人提供）：许多途径与心脏病有关，但对保持心脏健康的原因知之甚少。临床和实验研究记录了运动在预防和治疗心脏病方面的影响，包括缺血性损伤和心力衰竭（HF）。我们实验室先前的工作确定了由运动诱导的独特的“生理基因集”，以及该网络中的关键转录因子节点。值得注意的是，运动还激活了心脏中增殖和潜在再生的基因程序。基因模拟运动引起的变化足以概括运动心脏的许多表型特征，以及防止心衰。与转录因子一样，微rna （miRs）也调节大型基因表达网络并修饰复杂的心血管表型，但对它们在运动中的作用知之甚少。我们最近对运动小鼠心脏中差异表达的mir进行了全面筛选。在运动心脏中鉴定并验证了16个miRs的差异调节，然后进行了体外和体内功能分析。我们的初步数据表明，在两种独立的运动模型中，心脏miR-222被强烈上调，并似乎驱动心肌细胞（CMs）的增殖反应。本R21的总体目标是在体外和体内研究miR-222在CMs中的功能作用，并确定其下游机制。我们假设运动诱导内在信号变化，促进心脏健康，部分是通过促进再生，miR-222是这些益处的重要贡献者。我们将使用遗传和药理学干预的组合在体内测试这些假设，同时确定负责机制。如果成功，我们预计这些研究将为运动的益处和控制心脏再生能力的途径提供新的见解。此外，所生成的独特动物模型将为验证miR-222作为心脏病治疗靶点提供基础。

DESCRIPTION (provided by applicant): Many pathways have been implicated in heart disease, but less is understood about what keeps the heart healthy. Clinical and experimental studies document the impact of exercise in both preventing and treating heart disease, including ischemic injury and heart failure (HF). Prior work from our laboratory identified a distinct "physiological gene set" induced by exercise, as well as key transcription factor nodes in this network. Remarkably, exercise also activated a proliferative and potentially regenerative gene program in the heart. Genetically mimicking exercise-induced changes was sufficient to recapitulate many phenotypic features of the exercised heart, as well as to protect against HF. Like transcription factors, micro-RNAs (miRs) also regulate large gene expression networks and modify complex cardiovascular phenotypes but little is known about their role in exercise. We recently performed a comprehensive screen for miRs differentially expressed in hearts of exercised mice. Sixteen miRs were identified and validated as differentially regulated in exercised hearts, and then subjected to in vitro and in vivo functional assays. Our preliminary data demonstrate that cardiac miR-222 is robustly upregulated in two independent exercise models and appears to drive a proliferative response in cardiomyocytes (CMs). The overall goals of this R21 are to examine the functional roles of miR-222 in CMs in vitro and in vivo, and determine the downstream mechanisms. We hypothesize that exercise induces intrinsic signaling changes that promote cardiac health, in part by promoting regeneration, and that miR-222 is an important contributor to these benefits. We will use a combination of genetic and pharmacological interventions to test these hypotheses in vivo, while identifying the responsible mechanisms. If successful, we anticipate that these studies will provide new insights into the benefits of exercise and pathways controlling the regenerative capacity of the heart. In addition, the unique animal models generated will provide a foundation for validating miR-222 as a therapeutic target in cardiac disease.