Causes of Variability in Craniofacial Disease

描述（由申请人提供）：颅面疾病是一些最常见的人类出生缺陷，其严重程度和程度可能差异极大。颅面疾病有遗传和环境原因，很可能很大一部分疾病变异是由于基因/环境相互作用。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征（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），并且明显受到遗传调控。然而，我们缺乏对控制乙醇诱导的颅面疾病易感性的遗传位点的理解。我们已经利用了两个创新的遗传筛选来发现乙醇相互作用的基因座。这些筛选的结果表明血小板衍生生长因子受体a（pdgfra）和乙醇诱导的颌骨发育不全（eih）位点与乙醇协同作用。虽然未经处理的pdgfra突变体有腭裂，但我们的第一次遗传筛选表明，乙醇处理的pdgfra突变体有严重和广泛的颅面缺陷。此外，乙醇处理导致pdgfra杂合子的腭缺陷。我们已经证明，神经嵴细胞不能正常迁移在未经处理的pdgfra突变体，但在乙醇处理的pdgfra突变体和杂合子有细胞死亡的数量增加。在第二次遗传筛选中，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源性生长因子（Pdgf）家族成员调节颅面疾病的严重程度和范围。在目标2中，我们揭示了负责pdgfra在神经嵴细胞中独立的迁移和保护作用的细胞内信号事件。在目标3中，我们探索了eih如何与BMP信号通路相互作用，并确定了乙醇在多大程度上破坏了eih和BMP吗啉注射胚胎的内胚层发育。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与环境相互作用以调节人类颅面疾病严重程度的遗传位点提供关键见解。) 公共卫生相关性：几乎没有人知道基因-环境相互作用如何介导人类疾病。我们的研究将为基因/环境相互作用的机制提供一些初步的见解。我们获得的结果将直接转化为人类疾病，为关联研究提供候选位点，为遗传咨询和潜在治疗提供风险因素。

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. ) PUBLIC HEALTH RELEVANCE: Virtually nothing is known about how gene-environment interactions mediate human disease. Our studies will provide some of the very first insights into the mechanisms of gene/environment interactions. The results we obtain will translate directly to human disease, providing candidate loci for association studies, risk factors for genetic counseling and potential therapies.