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The role of RNA-binding protein Lin28a in hypertrophic cardiomyopathy

RNA结合蛋白Lin28a在肥厚型心肌病中的作用

基本信息

批准号：
10204792
负责人：
Jiandong Liu
金额：
$ 52.32万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2019-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204792
关键词：
Address Anabolism Animal Model Attention Attenuated Biogenesis Biological Process Cardiac Cardiac Myocytes Cause of Death Cell physiology Complex Data Development Developmental Process Disease Exhibits Gene Expression Gene Expression Profiling Gene Expression Regulation Genetic Genome Glycolysis Growth Health Heart Heart Hypertrophy Heart failure Hypertrophic Cardiomyopathy Hypertrophy In Vitro Knowledge Mediating Mediator of activation protein Messenger RNA Metabolic Metabolism Mitochondria Molecular Myocardial Norepinephrine Pathologic Pathway interactions Phenocopy Phenotype Phosphoenolpyruvate Carboxylase Physiological Play Post-Transcriptional Regulation Process Proteins RNA RNA-Binding Proteins Reagent Regulation Risk Factors Role Series Signaling Molecule Stimulus Structure Structure of molecular layer of cerebellar cortex Testing Tissues Transcript Transcriptional Regulation Translations base cell growth epigenetic regulation fatty acid oxidation gene function improved in vitro Model in vivo knock-down mRNA Stability metabolomics mortality novel overexpression pluripotency pressure public health relevance response sudden cardiac death tissue repair tool transcription factor transcriptome tumorigenesis

项目摘要

Abstract Pathological cardiac hypertrophy is a major risk factor of heart failure and sudden cardiac death, the leading cause of mortality in the US and worldwide. Despite substantial progress in our understanding of the molecular and physiological basis of this detrimental process, much remains to be learned. Cardiac hypertrophic response to pathological stimuli is a complex biological process that involves transcriptional, posttranscriptional and epigenetic regulation of the cardiac genome. RNA-binding protein (RBPs) constitutes a major layer of molecular regulation integral to the establishment of tissue transcriptomes. The RBPs play fundamental roles during both development and disease by regulating RNA biogenesis, structure, stability, transport and cellular localization. Among them, Lin28a was found to control many developmental and cellular processes including pluripotency, oncogenesis, tissue repair and metabolism via its role in increasing mRNA stability and/or translation efficiency. Although previous studies have implicated transcriptional factors and signaling molecules in pathological cardiac hypertrophy, the role of RBPs in this process received little attention. Through gene expression analysis, we found that Lin28a exhibited a dynamic expression during early stage of pathological cardiac hypertrophy. Cardiac specific deletion of Lin28a blunted pressure overload-induced cardiac hypertrophy. Likewise, in an in vitro model of cardiac hypertrophy, knockdown of Lin28a attenuated norepinephrine (NE)-induced hypertrophy, while overexpressing Lin28a alone was sufficient to enhance cardiomyocyte glycolysis and stimulate subsequent cardiomyocyte hypertrophic growth. Mechanistically, we found that Lin28a directly bound to the mRNA of Pck2, which encodes the mitochondrial phosphoenolpyruvate carboxykinase, and positively impacted its transcript level. Additionally, manipulation of Pck2 expression phenocopied the metabolic and hypertrophic phenotypes of manipulating Lin28a expression. Based on these observations, we hypothesize that Lin28a and its downstream mediator Pck2 act as crucial regulators of pathological cardiac hypertrophy via their roles in regulating cardiomyocyte metabolism. The aim of this proposal will leverage our series of unique tools, reagents, and animal models to elucidate the molecular and cellular pathways essential for the development of pathological cardiac hypertrophy. In doing so, we will address a central question concerning whether and how a metabolic switch to a more glycolytic phenotype during cardiac hypertrophy could contribute to the structural remodeling.

摘要