The role of Fgf8 during cardiovascular development

Fgf8 在心血管发育中的作用

• 批准号: 8272598
• 负责人: Anne M MOON
• 金额: $ 32.24万
• 依托单位: GEISINGER CLINIC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8272598
• 关键词: Ablation; Alleles; Behavior; Biological Assay; Candidate Disease Gene; Cardiovascular system; Cells; ChIP-seq; Chromatin; Computer Simulation; Congenital Abnormality; Congenital Heart Defects; Contractile Proteins; Data; Data Set; Defect; Development; Disease; Embryo; Endoderm; Fibroblast Growth Factor 8; Functional RNA; Gene Expression; Gene Targeting; Goals; Heart; Human; In Vitro; Indium; Ion Channel; Ligands; Live Birth; Maps; Molecular; Morphogenesis; Mutant Strains Mice; Myocardial; Myocardium; Nature; Neural Crest; Pathway interactions; Pattern; Phenotype; Population; Property; Regulatory Element; Research; Right ventricular structure; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Structure; Testing; Transgenic Organisms; Ventricular; Work; autocrine; base; cardiogenesis; cell motility; cell type; in vivo; malformation; member; mutant; novel; programs; public health relevance; receptor; research study; tool; transcription factor

DESCRIPTION (provided by applicant): Congenital heart defects occur in nearly 1% of human live births. Outflow tract malformations comprise nearly 40% of these and are lethal if unrepaired. Myocardium at the arterial pole of the heart in the outflow tract and right ventricle derives from a precursor population within the second heart field (SHF). We have discovered that Fibroblast Growth Factor 8 (Fgf8) operates high in a signaling cascade that regulates SHF behavior and the identity of outflow tract myocardial cells. These myocardial cells normally have a "nonworking" identity with specialized secretory, signaling and cell biologic functions that are critical for outflow tract morphogenesis. In Fgf8 conditional mouse mutants, many aspects of outflow tract myocardial identity are "mistaken"; the mutant myocardium does not perform the secretory and signaling functions required for downstream endothelial and neural crest behaviors during outflow tract remodeling. Our data support the overriding hypothesis that an autocrine Fgf signaling loop in the SHF is required for outflow tract myocardial precursors to correctly differentiate and achieve their unique identity. The goals of this proposal are to: determine the bases for distinct outflow tract (OFT) phenotypes seen after Fgf8 and Fgf receptor ablation in different temporospatial domains; identify Fgf8-dependent pathways in the SHF and in pharyngeal endoderm; define the identity of SHF-derived myocardial cells in Fgf8 mutant OFT and right ventricle; and discover direct transcriptional targets of Fgf8 effectors in the SHF. PUBLIC HEALTH RELEVANCE: The importance of Fibroblast Growth Factor 8 (Fgf8) function for embryonic cardiovascular development is well established, but the molecular and cellular mechanisms whereby this signaling protein regulates development of the heart are still unknown. The specific research objective is to determine how Fgf8 signaling to heart precursors controls the identity of their progeny in the outflow tract of the heart. We also seek to determine how Fgf8 influences the ability of the myocardial cells to perform signaling and secretory functions that are required for behavior of adjacent cell types during outflow tract development. This research is highly relevant to human birth defects and disease because congenital heart defects occur in nearly 1% of human live births and malformations of the outflow tract comprise nearly 40% of these and are lethal if unrepaired.

描述（由申请人提供）：近1%的人类活产婴儿存在先天性心脏缺陷。流出道畸形包括近40%，如果不修复是致命的。流出道和右心室中的心脏动脉极处的心肌细胞来源于第二心野（SHF）内的前体群体。我们已经发现成纤维细胞生长因子8（Fgf 8）在调节SHF行为和流出道心肌细胞的身份的信号级联中高度起作用。这些心肌细胞通常具有“非工作”特性，具有对流出道形态发生至关重要的专门分泌、信号传导和细胞生物学功能。在Fgf 8条件性小鼠突变体中，流出道心肌身份的许多方面是“错误的”;在流出道重塑期间，突变心肌不执行下游内皮和神经嵴行为所需的分泌和信号传导功能。我们的数据支持压倒一切的假设，即SHF中的自分泌Fgf信号环是流出道心肌前体细胞正确区分和实现其独特身份所必需的。该提案的目标是：确定不同的流出道（OFT）表型后，Fgf 8和Fgf受体消融在不同的时空域的基础;确定Fgf 8依赖的途径在SHF和咽内胚层;定义的身份SHF衍生的心肌细胞Fgf 8突变OFT和右心室;并发现直接转录靶点的Fgf 8效应在SHF。 公共卫生相关性：成纤维细胞生长因子8（Fgf 8）功能对胚胎心血管发育的重要性已得到充分证实，但这种信号传导蛋白调节心脏发育的分子和细胞机制仍然未知。具体的研究目标是确定Fgf 8信号传导到心脏前体如何控制其后代在心脏流出道中的身份。我们还试图确定FGF 8如何影响心肌细胞执行信号传导和分泌功能的能力，这些功能是流出道发育过程中相邻细胞类型行为所需的。这项研究与人类出生缺陷和疾病高度相关，因为先天性心脏缺陷发生在近1%的人类活产婴儿中，流出道畸形占其中近40%，如果不修复是致命的。