Posttranscriptional Regulation of RNA Binding Proteins in Heart Failure

心力衰竭中 RNA 结合蛋白的转录后调控

• 批准号: 10469455
• 负责人: Wei Guo
• 金额: $ 37.81万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469455
• 关键词: Achievement; Adult; Affect; Attenuated; Cardiac; Cardiac Myocytes; Cell Culture System; Clinical; Complex; Cultured Cells; DNA Sequence Alteration; Data; Defect; Development; Dilated Cardiomyopathy; Elderly; Event; Functional disorder; Gene Proteins; Genes; Genetic; Genetic Transcription; Heart; Heart failure; Hospitalization; Immunoprecipitation; Impairment; In Vitro; Induced Mutation; Knock-in; Knock-in Mouse; Knockout Mice; Lead; Link; Mass Spectrum Analysis; Mediating; Messenger RNA; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Muscle; Mutation; Pathogenesis; Pathologic; Patients; Phosphorylation; Phosphorylation Site; Pilot Projects; Post-Transcriptional Regulation; Prevention; Process; Protein Isoforms; Proteins; RNA; RNA Recognition Motif; RNA Splicing; RNA metabolism; RNA-Binding Proteins; Rattus; Regulation; Role; Series; Serine; Site; Systolic heart failure; Technology; Testing; Time; Transcript; Translations; Transportation; Untranslated RNA; Work; cofactor; conditional knockout; connectin; crosslink; fetal; heart function; in vivo; in vivo Model; inherited cardiomyopathy; inhibitor; innovation; insight; mRNA Precursor; mortality; mouse model; new therapeutic target; novel; novel therapeutics; nucleocytoplasmic transport; protein protein interaction; public health relevance; trafficking; transcriptome sequencing

Summary Heart failure is a major public heath issue worldwide and its morbidity and mortality are unacceptably high, and remains the leading cause of morbidity, mortality, and hospitalization among adults and the elderly. Given these clinical observations, development of new therapeutic targets is urgently required and understanding the molecular mechanisms responsible for heart failure development and progression is critically important to develop new therapeutic targets. For genes to produce their final functional products (proteins or non-coding RNAs), the RNA transcripts need to be extensively processed after transcription, including splicing, modification, transportation and translation. RNA binding proteins (RBPs) are important regulators in each step of the complex processes of RNA metabolism and are being recognized as emerging key players in the pathogenesis of heart failure. Although transcriptional changes have been extensively studied in the failing hearts, very little is known about the role of posttranscriptional events in the remodeling heart. In this proposal, we will systematically investigate the role of RNA binding protein 20 (RBM20) in the pathogenesis of heart failure. We hypothesize that RBM20 phosphorylation and mutations on phosphorylation sites alter the posttranscriptional process and lead to cardiac remodeling, and RBM20 isoforms and cofactors regulate fetal gene re-expression in adult heart to promote heart failure. To test the hypothesis, we have created mutation knock-in (KI) and double knockout mouse models to evaluate functional roles of posttranscriptional event changes in cardiac remodeling, and determine the genes and proteins affected by the posttranscriptional changes. KI mice will be used to evaluate the translational value with the inhibitor of nuclear transport for RBM20-meidated nucleo-cytoplasmic trafficking. Two specific aims are proposed in this proposal. 1) Determine the functional roles of RBM20 phosphorylation and genetic mutations on phosphorylation sites in the pathogenesis of heart failure; 2) Determine the molecular/cellular mechanisms of RBM20 mediated posttranscriptional regulation of heart failure through cofactors and RBM20 isoforms. The achievement of the proposed aims will gain new information regarding RBPs-mediated posttranscriptional regulation in the pathogenesis of heart failure and provide a new paradigm for the mechanistic study on genetic mutations- induced heart failure.

摘要 心力衰竭是世界范围内的一个主要公共卫生问题，其发病率和死亡率高得令人无法接受， 仍然是成人和老年人发病率、死亡率和住院的主要原因。vt.给出 这些临床观察，迫切需要开发新的治疗靶点，并认识到 导致心力衰竭发生和发展的分子机制对 开发新的治疗靶点。使基因产生其最终功能产物(蛋白质或非编码 RNA)，RNA转录本需要在转录后进行广泛的加工，包括剪接， 修改、运输和翻译。RNAbindingProteins(Rbp)是每一步的重要调节因子 RNA新陈代谢的复杂过程，并被认为是 心力衰竭的发病机制。尽管在失败的过程中转录变化已经被广泛研究 心脏，对转录后事件在心脏重塑中的作用知之甚少。在这份提案中， 我们将系统地研究RNA结合蛋白20(RBM20)在心脏发病中的作用 失败了。我们假设RBM20的磷酸化和磷酸化位点上的突变改变了 转录后过程并导致心脏重构，RBM20亚型和辅因子调节胎儿 成人心脏基因再表达促进心力衰竭。为了检验这一假设，我们创造了突变 敲入(KI)和双敲除小鼠模型评估转录后事件的功能作用 心脏重构的变化，并确定转录后影响的基因和蛋白 改变。KI小鼠将被用来评估核转运抑制剂的翻译价值 RBM20标记的核质运输。这项提案提出了两个具体目标。1)确定 RBM20磷酸化和磷酸化位点基因突变的功能作用 心衰的发病机制；2)确定RBM20介导的分子/细胞机制 通过辅因子和RBM20亚型对心力衰竭的转录后调控。取得的成就 提议的AIMS将获得关于限制性商业惯例介导的转录后调控的新信息 心力衰竭的发病机制，为基因突变的机制研究提供了新的范式 诱发心力衰竭。