Causes of Variability in Craniofacial Disease

颅面疾病变异的原因

• 批准号: 8462125
• 负责人: JOHANN K EBERHART
• 金额: $ 35.68万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462125
• 关键词: Alcohol consumption; Anterior; Apoptosis; Attenuated; Award; Bone Morphogenetic Proteins; Candidate Disease Gene; Cell Death; Cell physiology; Cleft Palate; Congenital Abnormality; Control Locus; Cytoplasmic Tail; Cytoprotection; Data; Defect; Development; Disease; Embryo; Endoderm; Environment; Ethanol; Event; Exhibits; Family member; Fetal Alcohol Syndrome; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic Screening; Heterozygote; Human; Individual; Jaw; Label; Ligands; Light; Maps; Mediating; Methods; Modeling; Mutation; Neural Crest Cell; Palate; Pathway interactions; Phenotype; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Play; Population; Predisposition; Risk Factors; Role; Screening Result; Severities; Severity of illness; Signal Pathway; Signal Transduction; Testing; Time; Transgenic Organisms; Translating; Variant; Zebrafish; alcohol exposure; attenuation; body system; cell motility; craniofacial; gain of function; gene environment interaction; gene function; human disease; innovation; insight; loss of function; migration; mutant; public health relevance; receptor; research study

DESCRIPTION (provided by applicant): Craniofacial diseases are some of the most common of human birth defects and can be extremely variable in their severity and extent. There are both genetic and environmental causes of craniofacial disease and it is likely that a large portion of disease variability is due to gene/environment interactions. It is our long-term objective to understand the mechanism of gene/environment interactions and how these interactions regulate disease severity. We have chosen to use Fetal Alcohol Syndrome (FAS) as a model of gene/environment interactions because FAS has variable craniofacial defects, has a known environmental cause (maternal alcohol consumption) and is clearly genetically regulated. However, we are lacking in our understanding of the genetic loci that control susceptibility to ethanol-induced craniofacial disease. We have utilized two innovative genetic screens to discover ethanol-interacting loci. Results from these screens demonstrate that the platelet-derived growth factor rector a (pdgfra) and ethanol-induced jaw hypoplasia (eih) loci interact synergistically with ethanol. While untreated pdgfra mutants have cleft palate, our first genetic screen demonstrated that ethanol-treated pdgfra mutants have profound and extensive craniofacial defects. Furthermore, ethanol-treatment causes palatal defects in pdgfra heterozygotes. We have shown that neural crest cells fail to migrate properly in untreated pdgfra mutants, but in ethanol treated pdgfra mutants and heterozygotes there is an increase in the amount of cell death. In a second genetic screen, we have found that ethanol-treated eih and Bone morphogenetic protein (Bmp) loss-of-function embryos have a jaw-loss phenotype similar to that in mutants that disrupt development of the anterior endoderm. Here, we determine the mechanisms for these interactions. In aim 1, we discover which Platelet-derived growth factor (Pdgf) family members regulate the severity and extent of craniofacial disease. In aim 2, we reveal the intracellular signaling events that are responsible for the separate migratory and protective roles that pdgfra plays in neural crest cells. In aim 3, we explore how eih interacts with the Bmp signaling pathway and we determine the extent to which ethanol disrupts endoderm development in eih and bmp morpholino injected embryos. Because of the conservation of gene function between zebrafish and humans, the results from our studies will provide key insights into the genetic loci that interact with the environment to modulate human craniofacial disease severity. )

描述（由申请人提供）：颅面疾病是最常见的人类出生缺陷之一，其严重程度和程度差异很大。颅面疾病既有遗传原因，也有环境原因，并且很可能很大一部分疾病变异是由于基因/环境相互作用造成的。我们的长期目标是了解基因/环境相互作用的机制以及这些相互作用如何调节疾病的严重程度。我们选择使用胎儿酒精综合症（FAS）作为基因/环境相互作用的模型，因为 FAS 具有可变的颅面缺陷，具有已知的环境原因（母亲饮酒）并且明显受到基因调控。然而，我们对控制乙醇引起的颅面疾病易感性的遗传位点缺乏了解。我们利用两种创新的基因筛选来发现与乙醇相互作用的位点。这些筛选的结果表明，血小板衍生生长因子受体 a (pdgfra) 和乙醇诱导的下颌发育不全 (eih) 基因座与乙醇具有协同相互作用。虽然未经处理的 pdgfra 突变体具有腭裂，但我们的第一次基因筛选表明，经乙醇处理的 pdgfra 突变体具有严重且广泛的颅面缺陷。此外，乙醇处理会导致 pdgfra 杂合子出现腭部缺陷。我们已经表明，在未经处理的 pdgfra 突变体中，神经嵴细胞无法正确迁移，但在乙醇处理的 pdgfra 突变体和杂合子中，细胞死亡量有所增加。在第二次基因筛选中，我们发现乙醇处理的 eih 和骨形态发生蛋白 (Bmp) 功能丧失胚胎具有与破坏前内胚层发育的突变体相似的下颌缺失表型。在这里，我们确定这些相互作用的机制。在目标 1 中，我们发现哪些血小板衍生生长因子 (Pdgf) 家族成员调节颅面疾病的严重程度和程度。在目标 2 中，我们揭示了细胞内信号传导事件，这些事件负责 pdgfra 在神经嵴细胞中发挥的单独的迁移和保护作用。在目标 3 中，我们探索了 eih 如何与 Bmp 信号通路相互作用，并确定乙醇破坏 eih 和 bmp 吗啉代注射胚胎中内胚层发育的程度。由于斑马鱼和人类之间基因功能的保守性，我们的研究结果将为了解与环境相互作用以调节人类颅面疾病严重程度的基因位点提供重要见解。 ）