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

基本信息

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
项目类别：
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

项目摘要

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) 的常见但并非普遍的先兆。也会因运动而生长，但这种称为生理性肥大的生长通常不会导致不良后果，甚至可以保护心脏免受病理应激。我们小组的研究表明，运动可以显着增强成人的内源性心肌生成我们对运动如何发挥其益处（包括对心脏的益处）的理解存在根本性差距。心肌细胞的增殖和潜在再生反应，以及为什么心脏肥大会产生我们的首要假设是，肥大有不同的形式。表面上看起来相似，但采用根本不同的机制，因此具有显着的差异我们的长期目标是了解造成这些差异和结果的途径。了解它们是否可以用于治疗当前应用的目的是了解。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，我们鉴定了 25 种受运动动态调节的心脏 lncRNA，我们将其术语长非编码练习相关成绩单或 lncExACT 与我们的总体一致。假设，在已识别的 25 个 lncExACT 中，运动和病理性肥大没有一致变化或 HF 中，五个 lncExACT 在疾病模型中也发生了改变，但与运动相比方向相反。其中之一，lncExACT1，特别有趣，因为它会减少运动的心脏并增加两者我们在动物心力衰竭模型和人类心力衰竭研究中的初步数据。体外和体内研究表明它作为生理和病理心脏之间的关键开关肥大并可能调节心肌细胞增殖，lncExACT1 似乎至少部分起作用，通过结合和抑制 microRNA miR-222，我们之前已经证明这是必要的生理性心脏生长和运动诱发的心肌发生。我们建议将这些研究扩展到三个综合具体目标，在目标 1 中，我们将全面综合。识别心肌细胞候选 lncRNA 并进行功能表征，这些 lncRNA 在运动中受到差异调节在目标 2 中，我们将与压力过载引起的病理性肥大和心力衰竭进行比较。表征 lncExACT1 在体内运动和压力超负荷以及遗传中的生物学作用在目标 3 中，我们将描述导致 lncExACT1 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。成功完成拟议的研究将增进我们对心脏肥大的理解和 HF，以及确定新的途径和潜在的治疗靶点，例如 lncExACT1，可以减轻这些临床上重要的病症并调节内源性心肌生成。