Mechanisms governing the differentiation and maintenance of atrial identity

心房特性分化和维持的机制

• 批准号: 10676430
• 负责人: Joshua Waxman
• 金额: $ 64.52万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676430
• 关键词: Adopted; Adult; Alleles; Arrhythmia; Atrial Heart Septal Defects; Binding Sites; Biological Assay; Cardiac; Cardiac Myocytes; Cause of Death; Child; Chromatin; Complication; Congenital Abnormality; Congenital Heart Defects; Data; Defect; Development; Differentiated Gene; EMSA; Electrophysiology (science); Embryo; Enhancers; Epigenetic Process; Etiology; FOXF1 gene; Failure; Foundations; Frequencies; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Epistasis; Genomics; Glean; Goals; Heart; Heart Atrium; Human; Luciferases; Maintenance; Molecular; Morbidity - disease rate; Mus; Mutation; Newborn Infant; Nuclear Hormone Receptors; Operative Surgical Procedures; Organ; Organogenesis; Orphan; Pacemakers; Patients; Prevalence; Reagent; Regulation; Regulatory Element; Repression; Signal Transduction; Sinoatrial Node; Sorting; Structural defect; Techniques; Testing; Tissues; Transgenic Organisms; Venous; Ventricular; Vertebrates; WNT Signaling Pathway; Work; Zebrafish; apoAI regulatory protein-1; cardiogenesis; chicken ovalbumin upstream promoter-transcription factor; gene regulatory network; genome editing; in vivo; loss of function; malformation; mortality; mutant; novel; novel strategies; novel therapeutics; overexpression; pharmacologic; prevent; single-cell RNA sequencing; transcription factor; transcriptomics; transdifferentiation

Project Summary/Abstract Appropriate differentiation and maintenance of cellular identity are required for normal development of all organs. In the heart, mutations in genes that are necessary to maintain cardiomyocyte identity are associated with structural congenital heart defects, which are the most common malformations found in newborns. Despite their frequency, the etiology of most congenital heart defects remains poorly understood. Furthermore, numerous structural congenital heart defects are associated with arrythmias. Although advances in surgical techniques have been successful in allowing patients to survive to adulthood, the surgeries do not repair arrythmias associated with the structural defects. Thus, it is essential to understand fundamental mechanisms directing normal vertebrate heart development, in order to inform us of the etiology of congenital heart defects and their associated arrythmias. A long-term goal of our lab is to understand the conserved molecular and genetic mechanisms that direct cardiac chamber size during early vertebrate development. Nr2f transcriptions factors have highly conserved requirements in vertebrate heart development. Furthermore, mutations in Nr2f genes in humans are associated with a spectrum of congenital heart defects, including atrial septal defects. This proposal will investigate fundamental mechanisms determining atrial chamber size through investigating Nr2f-dependent mechanisms controlling atrial cardiomyocyte differentiation and the maintenance of atrial cardiomyocyte identity. While requirements for Nr2f factors are well-established in atrial development, the mechanisms controlling Nr2f gene expression in atrial cardiomyocytes and by which Nr2f transcription factors direct atrial cardiomyocyte development remain poorly understood. Our work has shown that zebrafish Nr2f1a is the functional equivalent of Nr2f2 in atrial development. Our preliminary data has identified a conserved enhancer that that is sufficient to promote Nr2f1a expression in atrial cardiomyocytes zebrafish and that Nr2f1a has a previously unrecognized requirement concurrently maintaining atrial cardiomyocyte and inhibiting the acquisition of pacemaker cardiomyocyte identity. In Aim 1, we will interrogate the signals that regulate the conserved nr2f1a cis-regulatory enhancer that promotes atrial cardiomyocyte expression. In Aim 2, we will determine the temporal requirements of nr2f1a and the differentiation state of cardiomyocytes within the atria of nr2f1a mutants. In Aim 3, we will elucidate the Nr2f-dependent gene regulatory networks that repress pacemaker cardiomyocyte identity in venous atria. Our studies may provide a foundation of information that may inform us of the etiology of congenital heart defects and their associated arrythmias, which ultimately may lead to novel therapies that can prevent or ameliorate congenital heart defects and associated arrythmias in humans.

项目总结/文摘