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）是一种衰弱性疾病，包括所有乙醇引起的缺陷和疾病。据估计，在美国出生的儿童中，有超过1%的人患有这种疾病，他们的大脑和颅面骨骼都有缺陷。虽然胎儿暴露于乙醇中会导致FASD，但遗传因素也可能起作用。一种新的筛选方法用于鉴定基因/乙醇相互作用，以了解基因/乙醇相互作用如何影响疾病变异和严重程度。通过筛选现有的斑马鱼颅面突变体，鉴定出血小板衍生生长因子受体a （pdgfra）和成纤维细胞生长因子8a （fgf82）为乙醇敏感位点。初步数据表明，PI3K/AKT/mTOR通路中存在共同的相互作用机制，已知其促进细胞存活信号。在pdgfra相互作用中发现的缺陷的病因已经被彻底描述，并且需要进一步评估fgf8a/乙醇相互作用。本提案的目的是检验基因/乙醇相互作用影响FASD变异性和严重程度的假设。测试这一假设的三个目标包括：1)通过对两种突变体中PI3K/AKT/mTOR通路酶的免疫印迹分析基因/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/fgf8a颅面缺陷；3)阐明神经缺陷中fgf8a单倍不足，以及乙醇暴露时间如何加剧这些缺陷的严重程度。这些目标的结果将对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控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.