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

• 批准号: 10439474
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439474
• 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; 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

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 病理性心脏肥大是心力衰竭和心源性猝死的主要危险因素， 美国和全球的死亡原因。尽管我们在分子水平的理解上取得了实质性的进展， 和生理基础，这一有害的过程中，还有很多要了解。心脏肥大反应 病理刺激是一个复杂的生物过程，涉及转录，转录后和 心脏基因组的表观遗传调控。RNA结合蛋白（RBP）构成了一个主要的分子层 调节组织转录组的建立不可或缺。限制性商业惯例在这两个方面都发挥着重要作用。 通过调节RNA的生物发生、结构、稳定性、转运和细胞定位来控制发育和疾病。 其中，Lin 28 a被发现控制许多发育和细胞过程， 通过其在增加mRNA稳定性和/或翻译效率中的作用，促进肿瘤发生、组织修复和代谢。 虽然先前的研究已经暗示了转录因子和信号分子在病理性心脏病中的作用， 然而，在这一过程中，限制性商业惯例的作用很少受到关注。通过基因表达分析，我们 发现Lin 28 a在病理性心肌肥厚早期呈动态表达。心脏 Lin 28 a的特异性缺失减弱了压力超负荷诱导的心肌肥大。同样，在体外模型中， Lin 28 a基因敲低可减弱去甲肾上腺素（NE）诱导的心肌肥厚， 单独过表达Lin 28 a足以增强心肌细胞糖酵解并刺激随后的糖酵解。 心肌细胞肥大性生长。从机制上讲，我们发现Lin 28 a直接与Pck 2的mRNA结合， 编码线粒体磷酸烯醇丙酮酸羧激酶，并积极影响其转录 水平此外，pck 2表达的操作表型模仿了代谢和肥大表型， 操作Lin 28 a表达。基于这些观察结果，我们假设Lin 28 a及其下游的 介体Pck 2通过其在调节病理性心肌肥大中的作用而作为病理性心肌肥大的重要调节剂 心肌细胞代谢该提案的目的是利用我们的一系列独特的工具，试剂和动物 模型来阐明病理性心脏病发展所必需的分子和细胞途径， 肥厚在这样做时，我们将解决一个核心问题，即代谢是否以及如何转换为 心肌肥大时糖酵解表型增多可能导致结构重塑。