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。

基本信息

批准号：
10462155
负责人：
Logan Robert Jefferson Bailey
金额：
$ 4.2万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/10462155
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 Nucleus Cell Proliferation Cells Data Development Disease Dose Embryo Embryonic Heart Event Genes Genetic 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 experimental study fetal genetic approach genetic information in vivo in vivo regeneration insight loss of function mature animal new therapeutic target novel pluripotency postnatal postnatal development prenatal programs rational design regeneration potential response stem cells transcriptome transcriptome sequencing transcriptomics

项目摘要

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/总结。心肌细胞的细胞状态在出生后发育过程中发生显着改变。在此期间，心肌细胞最终分化，从根本上改变了它们的能量、功能机制和细胞生长的机制。尽管我们对控制胚胎心脏的因素已经有了很好的了解目前，我们对心肌细胞终末建立的机制还知之甚少。在出生后发育期间分化并在成人中维持这种细胞状态。至关重要的是，心肌细胞终末分化与心脏重塑和再生密切相关。虽然临终分化的转录组对于心肌细胞适应成人循环需求是必需的，这转录程序还抑制心肌细胞增殖，这是哺乳动物无能的基础心脏在受伤后有意义地再生。事实上，在心脏再生模型系统中，心肌细胞必须首先去分化并恢复到胎儿样转录组状态才能增殖。很少有研究考察负责维持心肌细胞终末分化的因素，但按理说，靶向心肌细胞终末分化的破坏可能揭示成人潜在的促增殖途径心脏并促进内源性心脏再生。在本研究中，我们将研究 RNA 结合蛋白 Muscleblind 样蛋白 1 (MBNL1) 在控制心肌细胞终末分化和心脏再生。虽然 MBNL1 表达 MBNL1 在心肌细胞终末分化过程中增加，已知可促进胎儿向成人亚型许多发育调控基因的转换，但从未被直接检查用于控制心肌细胞终末分化或整合到围绕心脏可塑性的调节机制中。具体来说，该提案将使用各种体内和体外遗传方法来解决以下问题目的：（1）确定MBNL1在维持成人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信息将表征 MBNL1 依赖的转录后调节机制控制心肌细胞终末分化，并将确定 MBNL1 是否可以用作新的促进内源性心脏再生的治疗目标。