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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.

病理性肥厚是心力衰竭（HF）的常见前兆，但并非普遍。心脏