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Role of pre-mRNA alternative splicing programs in heart and muscle development

前体 mRNA 选择性剪接程序在心脏和肌肉发育中的作用

基本信息

批准号：
8150611
负责人：
Andrea Nicole Ladd
金额：
$ 35.33万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8150611
关键词：
Adult Affect Alternative Splicing Binding Biological Models Cardiac Cardiac Myocytes Cell Culture Techniques Cells Chickens Coupled Cultured Cells Data Defect Development Diagnosis Disease Dominant-Negative Mutation Embryo Embryonic Development Embryonic Heart Equilibrium Event Exhibits Fiber Gene Expression Genes Goals Heart Heart Diseases In Vitro Individual Lead Light Mammals Mediating Molecular Molecular Biology Morphogenesis Morphology Mus Muscle Muscle Development Muscle Fibers Muscular Dystrophies Myocardium Myogenin Myopathy Myotonic Dystrophy Organism Pathogenesis Play Prevention Protein Family Protein Isoforms Proteins RNA Splicing Regulation Repression Reverse Transcriptase Polymerase Chain Reaction Role Site Skeletal Muscle Striated Muscles Symptoms Testing Training Transgenic Mice cardiogenesis cell motility fetal in vivo insight knock-down mRNA Precursor member mouse model programs promoter protein expression research study therapeutic target

项目摘要

Pre-mRNA alternative splicing is a common means by which cells generate multiple, functionally distinct isoforms from a single gene. Developmentally regulated splicing has been described individually for many genes, yet little is known about how programs of alternative splicing regulation contribute to embryonic development. Members of the CUG-BP and ETR-3-like factor (CELF) and muscleblind-like (MBNL) protein families have been shown to antagonistically regulate pre-mRNA alternative splicing in the heart. We hypothesize that CELF/MBNL-mediated alternative splicing programs play independent as well as overlapping roles in embryonic heart development. We have shown that changes in CELF and MBNL protein expression during cardiac morphogenesis are accompanied by transitions in alternative splicing. Additional preliminary data suggest that the CELF and/or MBNL proteins are critical for normal cardiac morphogenesis and function. The goal of this proposal is to elucidate the roles that CELF/MBNL-mediated alternative splicing programs play during embryonic heart development. We will use chicken and mouse model systems to investigate the effects of disrupting CELF/MBNL-mediated alternative splicing on cardiac morphogenesis and function, and identify the subset of pre-mRNAs subject to CELF/MBNL regulation in the heart. Understanding the roles that CELF/MBNL-mediated splicing programs play in normal embryonic heart development will provide insight into an understudied yet important mechanism of developmentally regulated gene expression. Furthermore, these studies will shed light on how disruption of normal alternative splicing contributes to disease states resulting from developmental perturbation

前体mRNA选择性剪接是细胞从单个基因产生多个功能不同的同种型的常见手段。发育调控剪接已被单独描述为许多基因，但很少有人知道如何程序的选择性剪接调控有助于胚胎发育。CUG-BP和ETR-3样因子（CELF）和肌盲样（MBNL）蛋白家族的成员已被证明可以拮抗性调节心脏中的前mRNA选择性剪接。我们假设CELF/MBNL介导的选择性剪接程序在胚胎心脏发育中发挥独立和重叠的作用。我们已经表明，在心脏形态发生过程中CELF和MBNL蛋白表达的变化伴随着选择性剪接的转换。额外的初步数据表明，CELF和/或MBNL蛋白对于正常的心脏形态发生和功能至关重要。该提案的目标是阐明CELF/MBNL介导的选择性剪接程序在胚胎心脏发育过程中发挥的作用。我们将使用鸡和小鼠模型系统来研究破坏CELF/MBNL介导的选择性剪接对心脏形态发生和功能的影响，并确定心脏中受CELF/MBNL调节的前体mRNA的子集。了解CELF/MBNL介导的剪接程序在正常胚胎心脏发育中发挥的作用，将提供深入了解发育调控基因表达的一个未充分研究但重要的机制。此外，这些研究将阐明正常的选择性剪接的破坏如何导致发育扰动引起的疾病状态