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: 10656393
• 负责人: Hasan Khatib
• 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/10656393
• 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; Genes; Genetic; Genetic Transcription; Heart; Heart failure; Hospitalization; Immunoprecipitation; Impairment; In Vitro; Induced Mutation; Knock-in; Knock-in Mouse; Knockout Mice; 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; Public Health; RNA; RNA Recognition Motif; RNA Splicing; RNA metabolism; RNA-Binding Proteins; Rattus; Regulation; Role; Series; Serine; Site; Systolic heart failure; Technology; Testing; Time; Transcript; Transcription Process; 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; mimetics; mortality; mouse model; new therapeutic target; novel; novel therapeutics; nucleocytoplasmic transport; posttranscriptional; 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.

总结 心力衰竭是世界范围内的主要公共健康问题，其发病率和死亡率高得不可接受， 仍然是成人和老年人发病、死亡和住院的主要原因。给定 根据这些临床观察，迫切需要开发新的治疗靶点，并了解 负责心力衰竭发生和进展的分子机制对于 开发新的治疗靶点。对于基因产生其最终功能产物（蛋白质或非编码蛋白质）， RNA），RNA转录物需要在转录后进行广泛的加工，包括剪接， 修改、运输和翻译。RNA结合蛋白（RBP）是这一过程的重要调节因子 RNA代谢的复杂过程，并被认为是新兴的关键球员， 心力衰竭的发病机制。虽然转录变化已经被广泛研究，在失败的 心脏，很少有人知道的作用，转录后事件在重塑心脏。在这一提议中， 本研究拟系统地探讨RNA结合蛋白20（RBM 20）在心脏病发病机制中的作用， 失败我们假设RBM 20磷酸化和磷酸化位点的突变改变了 RBM 20亚型和辅因子调节胎儿心肌细胞凋亡， 基因在成人心脏中的重新表达促进心力衰竭。为了验证这个假设，我们创造了突变 敲入（KI）和双敲除小鼠模型，以评估转录后事件功能作用 心脏重塑的变化，并确定受转录后影响的基因和蛋白质。 变化KI小鼠将用于评价核转运抑制剂的翻译值， RBM 20介导的核质运输。该提案提出了两个具体目标。1)确定 RBM 20磷酸化和磷酸化位点上的基因突变在细胞中的功能作用， 心力衰竭的发病机制; 2）确定RBM 20介导的心力衰竭的分子/细胞机制。 通过辅因子和RBM 20亚型对心力衰竭的转录后调节。的实现 提出的目标将获得有关RBP介导的转录后调控的新信息， 为基因突变的机制研究提供了新的范式- 导致心力衰竭。

项目成果

RBM20 phosphorylation and its role in nucleocytoplasmic transport and cardiac pathogenesis.

• DOI: 10.1096/fj.202101811rr
• 发表时间: 2022-05
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology

RBM20-Mediated Pre-mRNA Splicing Has Muscle-Specificity and Differential Hormonal Responses between Muscles and in Muscle Cell Cultures.

• DOI: 10.3390/ijms22062928
• 发表时间: 2021-03-13
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Maimaiti R;Zhu C;Zhang Y;Ding Q;Guo W
• 通讯作者: Guo W

Disruption of the nuclear localization signal in RBM20 is causative in dilated cardiomyopathy.

• DOI: 10.1172/jci.insight.170001
• 发表时间: 2023-07-10
• 期刊: JCI insight
• 影响因子: 8
• 作者: Zhang Y;Gregorich ZR;Wang Y;Braz CU;Zhang J;Liu Y;Liu P;Shen J;Aori N;Hacker TA;Granzier H;Guo W
• 通讯作者: Guo W