Maternal alcohol exposure: impact on genetic control of craniofacial phenotype

描述(申请人提供)：我是西雅图华盛顿大学儿科颅面内科博士后。我的研究兴趣在于了解人类畸形的机制(即基因和环境因素的作用)，特别是头面部疾病和正常的表型变异。考虑到这一点，我的目标是利用断层成像技术以及几何形态计量学作为一种定量评估头面部表型的手段。我申请这个K99/R00独立路径奖，长期目标是成为颅面畸形领域的一名独立研究员。我开发了一个研究项目，用数量遗传学和胚胎学来增强我在定量形态学和3D数字成像方面的背景，将自己转变为生物医学科学的独立研究员。作为实现这一目标的第一步，我将探索孕期酒精暴露对小鼠胚胎和出生后颅面发育的影响：(1)最先进的高分辨率活体显微CT和光学投影断层扫描；(2)传统的3D形状量化方法和新的3D网格变形方法来表征表型差异，以及(3)使用一种新的中等剂量慢性酒精暴露的小鼠模型，在成年人中产生Fas相关的可测量表型。本建议的长期目标是(1)通过详细量化颅面部表型，研究表观遗传编程在酒精相关畸形呈现中的作用，以及(2)将基因组差异与这些特征相关联，以找到导致表型差异的表观遗传修饰基因。未来，这些基因和在这个模型中修改它们的机制(S)可以转化为临床研究，并可能找到更好地诊断、甚至预防或规避酒精对胎儿发育的负面影响的方法。表观遗传编程在酒精相关表型中的作用将通过以下具体目标来解决：K1。探讨孕期酒精暴露对胚胎颅面发育的影响：K2。评估基因变异对颅面发育的影响。R1。研究妊娠期酒精暴露R2对胎儿头面部基因表达变化的影响。目的：探讨母亲饮酒对出生后颅面发育的纵向影响。开发生物信息学模型基础设施，以提供这项提案的数据和结果。华盛顿大学医学院和牙科学院在38个系拥有1800多名全职教职员工，其中包括8名诺贝尔奖获得者。今年，威斯康星州大学儿科系在《美国新闻与世界报道》中排名第六。 公共卫生相关性：胎儿酒精综合征是母亲饮酒的最极端后果，对健康具有相当大的重要性。胎儿接触乙醇导致结局高度不稳定的原因尚不清楚。这种不确定性可能与酒精暴露的剂量、时间和持续时间有关，也与种族、性别和母亲年龄的影响有关。了解影响颅面部形态的因素是改善胎儿酒精谱障碍诊断和治疗的关键步骤，并将有助于制定更有效的教育计划，说明母亲饮酒对胎儿和成人健康的不利影响。这些因素将通过一种独特的动物模型进行探索，并严格控制环境、剂量和遗传等混杂变量。

DESCRIPTION (provided by applicant): I am a postdoctoral fellow in the Division of Craniofacial Medicine, Department of Pediatrics, University of Washington in Seattle. My research interests lie in understanding the mechanisms (i.e. contributions of genes and environmental factors) responsible for human malformations, specifically craniofacial disorders, and normal phenotypic variation. With this in mind, my goal is to exploit tomographic imaging techniques as well as geometrics morphometrics as a means to quantitatively assess craniofacial phenotypes. I apply to this K99/R00 Pathways to Independence Award with the long-term goal becoming an independent researcher in the field of craniofacial dysmorphology. I have developed a research program to augment my background in quantitative morphology and 3D digital imaging with quantitative genetics and embryology to transition myself into an independent investigator in biomedical sciences. As the first step towards this goal, I will explore the effect of gestational alcohol exposure on the embryonic and post-natal craniofacial development of mice using: (1) state-of-the-art high-resolution in-vivo microCT and optical projection tomography, (2) traditional 3D shape quantification methods and a new 3D grid deformation methodology to characterize phenotypic differences, and (3) the use of a novel mouse model of moderate dose chronic ethanol exposure that produces FAS related measurable phenotypes in adults Long-term goals of this proposal are to (1) investigate the role of epigenetic programming in the presentation of alcohol-related malformations through detailed quantification of the craniofacial phenotype and (2) correlate genomic differences with these features to find epigenetically modified genes responsible for the phenotypic differences . In the future, these genes and the mechanism(s) by which they are modified in this model can be translated into clinical research and can offer the potential to find ways to better diagnose or even prevent or circumvent the negative effects of alcohol on fetal development. The role for epigenetic programming in alcohol-related phenotypes will be addressed through these specific aims: K1. To explore the effect of gestational alcohol exposure on embryonic craniofacial development: K2. To assess the impact of genetic variation on craniofacial development. R1. To characterize fetal craniofacial gene expression changes in response to gestational ethanol exposure R2. To explore the longitudinal effects of maternal alcohol consumption on post-natal craniofacial development R3. To develop a bioinformatics model infrastructure for making data and results from this proposal available. The University of Washington Schools of Medicine and Dentistry have over 1,800 full-time faculty members in 38 Departments, including 8 Nobel laureates. This year the UW Department of Pediatrics was ranked 6th by the US News and World Report among its peers. PUBLIC HEALTH RELEVANCE: Fetal alcohol syndrome represents the most extreme consequence of maternal alcohol consumption and is of considerable health importance. The reasons for the highly variable outcomes from fetal exposure to ethanol are unknown. The uncertainty might be related to dose, time and duration of ethanol exposure as well as the influence of race, gender and maternal age. Understanding the factors impacting on craniofacial form is an essential step to improve diagnosis and management of fetal alcohol spectrum disorders, and will significantly aid the development of more effective educational programs pertaining to the adverse effects of maternal alcohol consumption on fetal and adult health. These factors will be explored using a unique animal model and strictly controlling the confounding variables such as environment, dosage and genetics.