Gene/environment interactions underlying Fetal Alcohol Spectrum Disorder.

描述（由申请人提供）：FASD（胎儿酒精谱系障碍）是一种使人衰弱的疾病，包括所有乙醇诱导的缺陷和疾病。据估计，在美国出生的儿童中有超过1%受到影响，其缺陷会影响大脑和颅面骨骼。虽然胎儿暴露于乙醇会导致FASD，但遗传因素也可能起作用。一种新的屏幕被用来识别基因/乙醇的相互作用，以了解基因/乙醇的相互作用可能会影响疾病的变化和严重程度。通过筛选斑马鱼颅面突变体，确定血小板衍生生长因子受体a（pdgfra）和成纤维细胞生长因子8a（fgf 82）为乙醇敏感位点。初步数据表明，PI 3 K/AKT/mTOR信号通路中存在共同的相互作用机制，该通路促进细胞存活信号，pdgfra相互作用缺陷的病因学已被充分描述，fgf 8a/乙醇相互作用的进一步评估仍需进一步研究。本提案的目的是检验基因/乙醇相互作用影响FASD中发现的变异性和严重程度的假设。三个目标将包括测试该假设，包括：1）通过两种突变体中PI 3 K/AKT/mTOR途径中的酶的免疫印迹测定来分析基因/乙醇相互作用的机制; 2）通过原位表达分析和移植实验描述乙醇/fgf 8a颅面缺损; 3）阐明神经缺损中的fgf 8a单倍不足，以及乙醇暴露的时间如何加剧这些缺陷的严重性。这些目标的结果将在乙醇致畸学领域产生重大影响，为乙醇诱导疾病的病因学中涉及的遗传调节和相互作用机制提供新的见解。这将进一步促进FASD遗传咨询，诊断和治疗的进步。

DESCRIPTION (provided by applicant): FASD (Fetal Alcohol Spectrum Disorder) is a debilitating disease that encompasses all ethanol-induced defects and diseases. It is estimated to affect over 1% of children born in the United States, with defects affecting the brain and craniofacial skeleton. Although fetal exposure to ethanol causes FASD, genetic factors may contribute as well. A novel screen was used to identify gene/ethanol interactions to understand how gene/ethanol interactions may influence disease variation and severity. By screening available zebrafish craniofacial mutants, platelet derived growth factor receptor a (pdgfra) and fibroblast growth factor 8a (fgf82) were identified as ethanol sensitive loci. Preliminary data suggests that a common mechanism of interaction occurs in the PI3K/AKT/mTOR pathway, which is known to promote cell survival signals.The etiology of defects found in the pdgfra interaction have been thoroughly described, and further assessment of the fgf8a/ethanol interaction are needed. The purpose of this proposal is to test the hypothesis that gene/ethanol interactions influence variability and severity found in FASD. Three aims will encompass testing this hypothesis and include: 1) Analyzing the mechanism of gene/ethanol interaction through immunoblot assays of enzymes in the PI3K/AKT/mTOR pathway in both mutants; 2) Describing the ethanol/fgf8a craniofacial defects through in situ expression analysis and transplantation experiments, and 3) Elucidating fgf8a haploinsufficiency in neural defects, and how timing of ethanol-exposure exacerbates the severity of these defects. The results from these aims will have significant impact in the field of ethanol teratology, providing novel insight into both the genetic modulation and mechanism of interaction involved in the etiology of ethanol induced disease. This will further promote advancements in genetic counseling, diagnosis and treatment of FASD.