Causes of Variability in Craniofacial Disease

颅面疾病变异的原因

基本信息

批准号：
8268932
负责人：
JOHANN K EBERHART
金额：
$ 37.17万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
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/8268932
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

项目摘要

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.

描述（由申请人提供）：颅面疾病是人类出生缺陷中最常见的一些，其严重程度和程度可能极大。颅面疾病既有遗传和环境原因，很可能是由于基因/环境相互作用引起的大部分疾病变异性。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（母饮酒），并且在遗传上明确调节。但是，我们缺乏对控制乙醇诱导的颅面疾病敏感性的遗传基因座的理解。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，血小板衍生的生长因子菌群A（PDGFRA）和乙醇诱导的下颌促炎（EIH）基因座与乙醇协同相互作用。虽然未经处理的PDGFRA突变体的口感cle裂，但我们的第一个遗传筛查表明，经乙醇处理的PDGFRA突变体具有深刻而广泛的颅面缺陷。此外，乙醇治疗会导致PDGFRA杂合子中的pal骨缺陷。我们已经表明，神经rest细胞无法在未处理的PDGFRA突变体中正确迁移，但是在乙醇处理的PDGFRA突变体和杂合子中，细胞死亡量增加。在第二个遗传筛选中，我们发现经乙醇处理的EIH和骨形态发生蛋白（BMP）功能丧失的胚胎具有与破坏前内胚精发育的突变体相似的下颌表型。在这里，我们确定了这些相互作用的机制。在AIM 1中，我们发现哪种血小板衍生的生长因子（PDGF）家庭成员调节颅面疾病的严重程度和程度。在AIM 2中，我们揭示了PDGFRA在神经rest细胞中起作用的单独迁移和保护作用的细胞内信号传导事件。在AIM 3中，我们探讨了EIH如何与BMP信号通路相互作用，并确定乙醇在eiH和BMP Morpholino注射的胚胎中破坏内胚层发育的程度。由于斑马鱼和人类之间的基因功能保存，我们的研究结果将为与环境相互作用的遗传基因座提供关键的见解，以调节人类颅面疾病的严重程度。）公共卫生相关性：几乎对基因环境相互作用如何介导人类疾病一无所知。我们的研究将为基因/环境相互作用的机制提供一些最初的见解。我们获得的结果将直接转化为人类疾病，为关联研究，遗传咨询的危险因素和潜在疗法提供候选基因座。