Mechanisms governing the differentiation and maintenance of atrial identity

心房特性分化和维持的机制

基本信息

  • 批准号:
    10676430
  • 负责人:
  • 金额:
    $ 64.52万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Joshua Waxman其他文献

Joshua Waxman的其他文献

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{{ truncateString('Joshua Waxman', 18)}}的其他基金

Mechanisms underlying myxomatous valve disease
粘液瘤性瓣膜疾病的机制
  • 批准号:
    10455614
  • 财政年份:
    2021
  • 资助金额:
    $ 64.52万
  • 项目类别:
Mechanisms underlying myxomatous valve disease
粘液瘤性瓣膜疾病的机制
  • 批准号:
    10312919
  • 财政年份:
    2021
  • 资助金额:
    $ 64.52万
  • 项目类别:
Mechanisms underlying myxomatous valve disease
粘液瘤性瓣膜疾病的机制
  • 批准号:
    10611524
  • 财政年份:
    2021
  • 资助金额:
    $ 64.52万
  • 项目类别:
Molecular mechanisms of atrial development and regeneration
心房发育和再生的分子机制
  • 批准号:
    9363356
  • 财政年份:
    2017
  • 资助金额:
    $ 64.52万
  • 项目类别:
Molecular Mechanisms of Atrial Development and Regeneration
心房发育和再生的分子机制
  • 批准号:
    10601607
  • 财政年份:
    2017
  • 资助金额:
    $ 64.52万
  • 项目类别:
Coup-tf dependent mechanisms of ventricular and hemangioblast specification
心室和成血管细胞规范的 Coup-tf 依赖性机制
  • 批准号:
    8435042
  • 财政年份:
    2013
  • 资助金额:
    $ 64.52万
  • 项目类别:
Coup-tf dependent mechanisms of ventricular and hemangioblast specification
心室和成血管细胞规范的 Coup-tf 依赖性机制
  • 批准号:
    8819146
  • 财政年份:
    2013
  • 资助金额:
    $ 64.52万
  • 项目类别:
Coup-tf dependent mechanisms of ventricular and hemangioblast specification
心室和成血管细胞规范的 Coup-tf 依赖性机制
  • 批准号:
    8606886
  • 财政年份:
    2013
  • 资助金额:
    $ 64.52万
  • 项目类别:
Coup-tf dependent mechanisms of ventricular and hemangioblast specification
心室和成血管细胞规范的 Coup-tf 依赖性机制
  • 批准号:
    9031127
  • 财政年份:
    2013
  • 资助金额:
    $ 64.52万
  • 项目类别:
Elucidation of molecular networks required to limit cardiac cell number
阐明限制心肌细胞数量所需的分子网络
  • 批准号:
    8111233
  • 财政年份:
    2010
  • 资助金额:
    $ 64.52万
  • 项目类别:

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