Micro-RNA regulation of the cardiac exercise response

心脏运动反应的微小RNA调节

基本信息

批准号：
8459721
负责人：
ANTHONY ROSENZWEIG
金额：
$ 26.1万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459721
关键词：
Animal Model Bioinformatics Biological Assay Biological Markers CDKN1B gene Cardiac Cardiac Myocytes Cardiovascular system Cell Cycle Chronic Disease Clinical Clinical Research Complex Data Development Disease Progression Exercise Foundations Functional RNA Future Gene Expression Genes Genetic Goals Grant Health Heart Heart Diseases Heart failure In Vitro Injury Intervention Investigation Laboratories Lead Mediating Mediator of activation protein MicroRNAs Modeling Morbidity - disease rate Mus Myocardial Ischemia Natural regeneration Pathway interactions Patients Phenotype Physiological Reagent Regulation Risk Rodent Role Running Signal Transduction Stimulus Swimming Testing Tetracyclines Therapeutic Transgenic Organisms Work cyclin-dependent kinase inhibitor 1B fitness gain of function in vivo inhibitor/antagonist insight locked nucleic acid loss of function mortality novel novel therapeutic intervention outcome forecast prevent programs public health relevance regenerative research study response therapeutic target transcription factor

项目摘要

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.

描述（由申请人提供）：许多途径与心脏病有关，但对于如何保持心脏健康却知之甚少。临床和实验研究证明了运动对预防和治疗心脏病（包括缺血性损伤和心力衰竭 (HF)）的影响。我们实验室之前的工作确定了运动诱导的独特“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的增殖和潜在再生基因程序。基因模拟运动引起的变化足以重现运动心脏的许多表型特征，并预防心力衰竭。与转录因子一样，微小 RNA (miR) 也调节大型基因表达网络并改变复杂的心血管表型，但人们对其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。鉴定并验证了 16 个 miR 在运动心脏中的差异调节，然后进行体外和体内功能测定。我们的初步数据表明，心脏 miR-222 在两个独立的运动模型中显着上调，并且似乎驱动心肌细胞 (CM) 的增殖反应。该 R21 的总体目标是在体外和体内检查 miR-222 在 CM 中的功能作用，并确定下游机制。我们假设运动会诱导内在信号变化，从而促进心脏健康，部分是通过促进再生，而 miR-222 是这些益处的重要贡献者。我们将结合遗传和药理学干预措施在体内测试这些假设，同时确定相关机制。如果成功，我们预计这些研究将为运动的好处和控制心脏再生能力的途径提供新的见解。此外，生成的独特动物模型将为验证 miR-222 作为心脏病的治疗靶点奠定基础。