Discovery and characterization of lncRNAs involved in cardiac exercise phenotypes

参与心脏运动表型的 lncRNA 的发现和表征

• 批准号: 9885953
• 负责人: ANTHONY ROSENZWEIG
• 金额: $ 39.96万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9885953
• 关键词: Adult; Animals; Binding; Biological; Biomechanics; Birth; Cardiac; Cardiac Myocytes; Cell Cycle; Clinical; Data; Dilated Cardiomyopathy; Disease model; Exercise; Gene Expression; Genetic; Genetic Models; Genetic Transcription; Genomics; Goals; Growth; Health; Heart; Heart Hypertrophy; Heart failure; Human; Hypertrophy; Image; In Vitro; Inherited; Isotopes; Knowledge; Lead; Learning; Mass Spectrum Analysis; Mediating; MicroRNAs; Mission; Modeling; Mus; National Heart, Lung, and Blood Institute; Natural regeneration; Outcome; Pathologic; Pathway interactions; Patients; Phenotype; Physiological; Proliferation Marker; Proteins; Public Health; RNA; Regenerative response; Research; Role; Running; Serum; Stress; Therapeutic; Transcript; United States National Institutes of Health; Untranslated RNA; Work; adverse outcome; cardioprotection; genome-wide analysis; in vivo; inhibitor/antagonist; loss of function; myogenesis; novel; physiologic model; pressure; prevent; programs; promoter; protective effect; response; therapeutic target; transcription factor; transcriptome sequencing; virtual

Pathological hypertrophy is a common but not universal predecessor to heart failure (HF). The heart also grows in response to exercise but this growth, termed physiological hypertrophy, does not generally lead to adverse consequences and can even protect the heart against pathological stress. Moreover, recent work from our group demonstrates that exercise substantially enhances endogenous cardiomyogenesis in the adult heart. There is a fundamental gap in our understanding of how exercise mediates its benefits, including a proliferative and potentially regenerative response in cardiomyocytes, and why cardiac hypertrophy can have such different outcomes. Our over-arching hypothesis is that there are distinct forms of hypertrophy, which appear superficially similar but employ fundamentally different mechanisms and thus have dramatically different outcomes. Our long-term goal is to understand the pathways responsible for these differences and learn whether they can be exploited therapeutically. The objective of the current application is to understand the role of long noncoding RNAs (lncRNAs) in exercise-associated cardiac phenotypes. In preliminary studies, we identified 25 cardiac lncRNAs dynamically regulated by exercise, which we term long noncoding Exercise Associated Transcripts or lncExACTs. Consistent with our over-arching hypothesis, of the 25 lncExACTs identified, none change concordantly in exercise and pathological hypertrophy or HF. Five lncExACTs are also altered in the disease models – but in opposite directions compared to exercise. One of these, lncExACT1, is particularly intriguing because it decreases in exercised hearts and increases both in animal HF models and human HF. Our preliminary data with lncExACT1 gain- and loss-of-function studies in vitro and in vivo suggest it functions as a pivotal switch between physiological and pathological cardiac hypertrophy and may regulate cardiomyocyte proliferation. lncExACT1 appears to work, at least in part, through binding and inhibiting the microRNA, miR-222, which we have previously shown is necessary for physiological cardiac growth and exercise-induced cardiomyogenesis. We propose to extend these studies in three integrated Specific Aims. In Aim 1, we will comprehensively identify and functionally characterize in cardiomyocytes candidate lncRNAs differentially regulated in exercised hearts in comparison to pressure-overload induced pathological hypertrophy and HF. In Aim 2, we will characterize the biological roles of lncExACT1 in vivo in exercise and pressure-overload, as well as in a genetic model of dilated cardiomyopathy. In Aim 3, we will delineate the mechanisms responsible for lncExACT1’s cardiac effects, including binding to miRNAs and proteins as well as local genomic effects on gene expression. Successful completion of the proposed studies will advance our understanding of cardiac hypertrophy and HF, as well as identifying novel pathways and potential therapeutic targets, such as lncExACT1, that can mitigate these clinically important conditions and regulate endogenous cardiomyogenesis.

病理性肥厚是心力衰竭(HF)的常见但并不普遍的前身。心脏 也会随着运动而生长，但这种生长，称为生理性肥大，通常不会导致 对不良后果，甚至可以保护心脏免受病理性压力。此外，最近的工作 来自我们小组的研究表明，锻炼大大增强了成年人的内源性心肌生成 心。在我们对运动如何调节其益处的理解上存在着根本的差距，包括 心肌细胞的增殖和潜在的再生反应，以及为什么心肌肥厚会有 结果如此不同。我们最重要的假设是，有不同形式的肥厚， 表面上看起来很相似，但使用了根本不同的机制，因此有很大的 不同的结果。我们的长期目标是了解导致这些差异的途径，并 了解它们是否可以用于治疗。当前应用程序的目标是理解 长非编码RNA(LncRNA)在运动相关心脏表型中的作用。 在初步研究中，我们确定了25个受运动动态调节的心脏lncRNA，我们 长期非编码练习相关转录本或LncExACT。与我们的最高拱门 假设，在已确定的25个lncExACT中，没有一个在运动和病理性肥厚中发生一致的变化 或者HF。在疾病模型中，五个lncExACT也发生了改变--但与锻炼相比，改变的方向相反。 其中，lncExACT1特别耐人寻味，因为它在锻炼后的心脏中减少，而在锻炼后的心脏和心脏中都增加。 在动物心力衰竭模型和人类心力衰竭模型中。我们使用InncExACT1增减功能研究的初步数据 体外和体内研究表明，它在生理和病理心脏之间起着关键的开关作用。 肥大，可能调节心肌细胞的增殖。至少在一定程度上，LncExACT1似乎起作用了， 通过结合和抑制microRNA，miR-222，我们之前已经证明是必要的 生理性心脏生长和运动诱导的心肌生成。 我们建议将这些研究扩展到三个综合的具体目标。在目标1中，我们将全面 运动中差异调控的心肌细胞候选基因的鉴定和功能特征 心脏与压力超负荷所致病理性肥厚和心衰的比较。在目标2中，我们将 描述lncExACT1在体内在运动和压力超负荷以及在遗传中的生物学作用 扩张型心肌病模型。在目标3中，我们将描述导致InncExACT1‘S’的机制 心脏效应，包括与miRNAs和蛋白质的结合以及局部基因组对基因表达的影响。 成功完成拟议的研究将促进我们对心肌肥厚的理解 以及识别新的通路和潜在的治疗靶点，如lncExACT1，它们可以 缓解这些临床上重要的疾病，调节内源性心肌生成。