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Molecular mechanisms of atrial development and regeneration

心房发育和再生的分子机制

基本信息

批准号：
9363356
负责人：
Joshua Waxman
金额：
$ 39.75万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-21 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9363356
关键词：
3&apos Untranslated Regions ATAC-seq Ablation Adult Affect Affinity Chromatography Antisense RNA Arrhythmia Biological Assay Birth CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Lineage Cell Transplantation Cells Cessation of life Child Chromatin Complex Congenital Abnormality Congenital Heart Defects Data Defect Development Diagnosis Disease Embryo Engineering Epigenetic Process Ethylnitrosourea Etiology Foundations Gene Expression Regulation Generations Genetic Complementation Test Genomics Glean Goals Health Heart Heart Atrium Heart Hypertrophy Heart Injuries Human Impairment In Vitro Individual Knockout Mice Knowledge Life Methods MicroRNAs Modeling Molecular Morphology Mus Mutagenesis Mutation Natural regeneration Neonatal Mortality Newborn Infant Nuclear Hormone Receptors Nuclear Orphan Receptor Orphan Pathway interactions Play Positioning Attribute Prevalence Production Proteins RNA Ribosomes Role Signal Transduction Site Stroke Surface Techniques Testing Tissues Transcript Transcriptional Activation Translations Transposase Untranslated RNA Ventricular Vertebrates Zebrafish apoAI regulatory protein-1 atrioventricular septal defect blastocyst cardiac regeneration cardiogenesis genome editing healing human stem cells improved in utero diagnosis in vivo inhibitor/antagonist injured loss of function mutant next generation sequencing novel novel therapeutics premature prevent progenitor promoter regenerative repaired transcription factor transcriptome sequencing

项目摘要

Project Summary/Abstract Congenital heart defects (CHDs) are the most common congenital malformations. 5% of CHDs comprise atrioventricular septal defects (AVSDs). However, the molecular etiology underlying most AVSDs are not understood. Furthermore, CHDs can cause cardiovascular diseases later in life, resulting in arrhythmias, stroke, and premature death. In order to develop novel therapies able to prevent CHDs and heal specific cardiovascular tissues, it is critical to garner understanding of fundamental mechanisms directing normal cardiac chamber development and regeneration. Therefore, long-term goals of our lab are to understand conserved mechanisms that direct the development of the individual cardiac chambers and chamber-specific mechanisms of regeneration in vertebrates. Few signals are known to be required that specifically direct atrial development, with specific regulators of atrial regeneration not being understood. The specific aims of this proposal are to elucidate the mechanisms by which a syntenic long non-coding RNA (lncRNA) as-oca restricts atrial development and regeneration through inhibition of Nr2f1a translation in zebrafish. The studies in this proposal are relevant to human health as recent genomic analysis indicates that mutations in the orphan nuclear receptor Nr2f2 are associated with AVSDs in humans. While Nr2f2 knockout mice and in vitro studies with human stem cells have revealed requirements for both Nr2f1 and Nr2f2 in atrial development, the mechanisms by which Nr2f proteins direct proper atrial development are not completely understood. Importantly, there is currently no understanding of epigenetic lncRNA-dependent mechanisms regulating Nr2f proteins. Our preliminary analysis of the novel zebrafish mutant acorn worm (aco) indicate that excess expression of as-oca specifically restricts the addition of later differentiating second heart field (SHF)-derived atrial cells. In Aim 1, we will use blastula cell transplantation, in vivo cardiomyocyte differentiation assays, and genome editing to determine the cellular requirements underlying the atrial defects and cause of increased as- oca expression in aco mutants. We do not understand how as-oca inhibits Nr2f1a translation in aco mutants. In Aim 2, we will use RNA and ribosomal association techniques and loss of function methods to determine if as- oca inhibits Nr2f1a translation through interactions with the nr2f1a 3' untranslated region. In addition to their requirements during development, we find that as-oca and nr2f1a are specifically expressed in the atria of adult zebrafish. In Aim 3, we will test the effects of as-oca on embryonic and adult models of cardiac regeneration. Because Nr2f transcription factors play conserved roles in atrial development of all vertebrates, these studies will dramatically improve our understanding of posttranscriptional mechanisms regulating normal vertebrate atrial development and the molecular etiology of AVSDs and ASDs in humans. Ultimately, these studies will generate a foundation for improved therapies capable of preventing CHDs in children and efficiently repairing injured hearts in adults.

项目总结/文摘