Investigating the Role of MBNL1 in Maintaining Cardiomyocyte Terminal Differentiation.

研究 MBNL1 在维持心肌细胞终末分化中的作用。

• 批准号: 10700835
• 负责人: Logan Robert Jefferson Bailey
• 金额: $ 4.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2026-09-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700835
• 关键词: Acute; Address; Adult; Biological; Biological Assay; Biological Models; Biology; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Cycle; Cell Differentiation process; Cell Proliferation; Cells; Data; Development; Disease; Dose; Embryo; Embryonic Heart; Event; Experimental Genetics; Genes; Genetic Models; Genetic Transcription; Glean; Growth; Heart; Heart Diseases; Heart failure; High-Throughput RNA Sequencing; Hypertrophy; In Vitro; Injury; Ions; Knock-out; Knowledge; Link; Maintenance; Messenger RNA; Metabolic; Modeling; Molecular Biology; Molecular Target; Mus; Muscle; Myocardial Infarction; Natural regeneration; Neonatal; Outcome; Pathway interactions; Play; Post-Transcriptional Regulation; Process; Proliferating; Protein Isoforms; Proteins; RNA; RNA Splicing; RNA-Binding Proteins; Regenerative Medicine; Regenerative capacity; Regulation; Role; Tamoxifen; Testing; Therapeutic Uses; Time; Transcript; Transcriptional Regulation; cardiac regeneration; cardiogenesis; cell behavior; cell growth; cell type; critical developmental period; fetal; gain of function; genetic approach; genetic information; in vivo; in vivo regeneration; insight; loss of function; mature animal; new therapeutic target; novel; pluripotency; postnatal; postnatal development; posttranscriptional; prenatal; programs; rational design; regeneration potential; response; single nucleus RNA-sequencing; stem cells; transcriptome; transcriptomics

PROJECT ABSTRACT/SUMMARY. Cardiomyocyte cell state is dramatically altered during postnatal development. During this period, cardiomyocytes terminally differentiate, fundamentally changing their energetics, functional machinery, and mechanism of cell growth. Although we have a good understanding of the factors controlling embryonic heart development, we still have a poor understanding of the mechanisms that establish cardiomyocyte terminal differentiation during postnatal development and maintain this cell state in the adult. Critically, cardiomyocyte terminal differentiation is integrally linked to cardiac remodeling and regeneration. While a terminally differentiated transcriptome is necessary for cardiomyocytes to accommodate adult circulatory demands, this transcriptional program also suppresses cardiomyocyte proliferation, underlying the inability of the mammalian heart to meaningfully regenerate after injury. Indeed, in model systems of cardiac regeneration, cardiomyocytes must first de-differentiate and return to a fetal-like transcriptomic state in order to proliferate. Few studies examine the factors responsible for maintaining cardiomyocyte terminal differentiation, but it stands to reason that targeted disruption of cardiomyocyte terminal differentiation could unmask latent pro-proliferative pathways in the adult heart and promote endogenous cardiac regeneration. In this study, we will examine the role of the RNA-binding protein Muscleblind-like protein 1 (MBNL1) in controlling cardiomyocyte terminal differentiation and cardiac regeneration. Although MBNL1 expression increases during cardiomyocyte terminal differentiation and MBNL1 is known to promote fetal-to-adult isoform switching of a number of developmentally regulated genes, it has never been examined directly for controlling cardiomyocyte terminal differentiation or integrated into regulatory mechanisms surrounding cardiac plasticity. Specifically, this proposal will use a variety of in vivo and in vitro genetic approaches to address the following aims: (1) to determine the role of MBNL1 in maintaining cardiomyocyte terminal differentiation in the adult mammalian heart and (2) to determine the role of MBNL1 in controlling cardiac regenerative potential. Insight gleaned from these aims will characterize MBNL1-dependent post-transcriptional regulatory mechanisms governing cardiomyocyte terminal differentiation and will determine if MBNL1 could be used as a novel therapeutic target to promote endogenous cardiac regeneration.

项目摘要/摘要。 心肌细胞态在产后发育过程中发生了巨大变化。在此期间， 心肌细胞在终极区分，从根本上改变其能量，功能机械和 细胞生长的机制。尽管我们对控制胚胎心脏的因素有很好的了解 开发，我们仍然对建立心肌细胞末端的机制有不良的理解 产后发育过程中的分化并维持成人的细胞状态。至关重要的是心肌细胞 末端分化与心脏重塑和再生完全相关。而最终 差异化转录组对于适应成人循环需求的心肌细胞是必需的 转录程序还抑制了心肌细胞的增殖，这是哺乳动物的无力 受伤后有意义地再生的心。实际上，在心脏再生模型系统中，心肌细胞 必须首先去分化并返回到类似胎儿的转录组状态才能增殖。很少有研究检查 负责维持心肌细胞末端分化的因素，但这是有针对性的理由 心肌细胞终末分化的破坏可能会揭露成人潜在的促增殖途径 心脏并促进内源性心脏再生。 在这项研究中，我们将研究RNA结合蛋白肌肉闪光蛋白1（MBNL1）在 控制心肌细胞末端分化和心脏再生。虽然MBNL1表达 众所周知，心肌细胞末端分化和MBNL1的增加会促进胎儿至成年的同工型 转换多个受发展调控的基因，从未直接检查过它的控制 心肌细胞末端分化或整合到心脏可塑性周围的调节机制中。 具体而言，该建议将使用各种体内和体外遗传方法来解决以下 目的：（1）确定MBNL1在成年人中心肌细胞终末分化中的作用 哺乳动物心脏和（2）确定MBNL1在控制心脏再生潜力中的作用。洞察力 从这些目标中收集的将表征依赖MBNL1的转录后调节机制 治理心肌细胞终末分化，并将确定是否可以将MBNL1用作新颖 促进内源性心脏再生的治疗靶标。