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.

病理性肥大是心力衰竭（HF）的常见但不普遍的前驱症状。心脏 也会因运动而增长，但这种增长，称为生理性肥大，通常不会导致 甚至可以保护心脏免受病理性压力。此外，最近的工作 我们小组的研究表明，运动能显著增强成年人的内源性心肌细胞生成， 心我们对运动如何调节其益处的理解存在根本性的差距，包括 增殖和潜在的再生反应，以及为什么心脏肥大可以 如此不同的结果。我们的过度假设是，有不同形式的肥大， 表面上看起来相似，但采用根本不同的机制，因此具有显着的 不同的结果。我们的长期目标是了解造成这些差异的途径， 了解它们是否可以用于治疗。本申请的目的是理解 长链非编码RNA（lncRNA）在运动相关心脏表型中的作用。 在初步研究中，我们鉴定了25种由运动动态调节的心肌lncRNA， 长期非编码运动相关转录本或lncExACT。与我们过度的 假设，在确定的25种lncExACT中，运动和病理性肥大均无一致变化 或HF。五种lncExACT在疾病模型中也发生了变化-但与运动相比方向相反。 其中之一，lncExACT 1，是特别有趣的，因为它减少了运动的心脏和增加两者 在动物HF模型和人HF中。我们对lncExACT 1功能获得和丧失研究的初步数据 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 肥大并可调节心肌细胞增殖。lncExACT 1似乎起作用，至少部分起作用， 通过结合和抑制microRNA，miR-222，我们以前已经证明，这是必要的， 生理性心脏生长和运动诱导的心肌发生。 我们建议在三个综合具体目标中扩展这些研究。目标1：全面 在心肌细胞中鉴定和功能表征在运动中差异调节候选lncRNA 与压力超负荷诱导的病理性肥大和HF相比，在目标2中，我们将 描述lncExACT 1在体内运动和压力超负荷中的生物学作用，以及在遗传学上的作用。 扩张型心肌病模型。在目标3中，我们将描述负责lncExACT 1的机制。 心脏效应，包括与miRNA和蛋白质的结合以及对基因表达的局部基因组效应。 这些研究的成功完成将促进我们对心肌肥大的认识 和HF，以及识别新的途径和潜在的治疗靶点，如lncExACT 1， 减轻这些临床上重要的病症并调节内源性心肌发生。