The role of Fgf8 during cardiovascular development

Fgf8 在心血管发育中的作用

基本信息

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
项目类别：
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

项目摘要

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% 的人类活产婴儿患有先天性心脏病。其中近 40% 为流出道畸形，如果不及时修复，将会致命。流出道和右心室中心脏动脉极的心肌源自第二心区 (SHF) 内的前体群体。我们发现成纤维细胞生长因子 8 (Fgf8) 在调节 SHF 行为和流出道心肌细胞身份的信号级联中发挥着重要作用。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特殊分泌、信号传导和细胞生物学功能。在Fgf8条件小鼠突变体中，流出道心肌身份的许多方面都是“错误的”；突变心肌在流出道重塑过程中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。我们的数据支持最重要的假设，即 SHF 中的自分泌 Fgf 信号环路是流出道心肌前体细胞正确区分并实现其独特身份所必需的。该提案的目标是：确定不同时空域中 Fgf8 和 Fgf 受体消融后观察到的不同流出道 (OFT) 表型的基础；确定 SHF 和咽内胚层中 Fgf8 依赖性途径；确定 Fgf8 突变体 OFT 和右心室中 SHF 衍生心肌细胞的身份；并发现 SHF 中 Fgf8 效应子的直接转录靶点。公共健康相关性：成纤维细胞生长因子 8 (Fgf8) 功能对胚胎心血管发育的重要性已得到充分证实，但这种信号蛋白调节心脏发育的分子和细胞机制仍不清楚。具体研究目标是确定 Fgf8 信号传导至心脏前体细胞如何控制其后代在心脏流出道中的身份。我们还试图确定 Fgf8 如何影响心肌细胞执行流出道发育过程中相邻细胞类型行为所需的信号传导和分泌功能的能力。这项研究与人类出生缺陷和疾病高度相关，因为先天性心脏病发生在近 1% 的人类活产儿中，而流出道畸形占其中近 40%，如果不修复的话会致命。