Maternal alcohol exposure: impact on genetic control of craniofacial phenotype

项目摘要 我是加州大学儿科头面部医学部博士后 华盛顿在西雅图。我的研究兴趣在于了解机制(即。基因的贡献 和环境因素)导致人类畸形，特别是头面部疾病，以及 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定量评估头面部表型的一种手段。我适用于此 K99/R00独立之路奖，长期目标是成为一名独立研究员 颅面畸形学领域。我已经制定了一个研究计划，以增强我在 用数量遗传学和胚胎学的数量形态和3D数字成像来转变我自己 成为生物医学科学领域的独立研究员。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)最先进的高分辨率在体显微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，该模型产生Fas相关的 成人的可测量表型 这项提案的长期目标是(1)调查表观遗传编程在呈现 酒精相关畸形通过详细量化头面部表型和(2)相关 基因组差异与这些特征寻找表观遗传修饰的基因负责的表型 分歧。在未来，这些基因和它们在这个模型中被修改的机制(S)可以 转化为临床研究，可以提供找到更好地诊断甚至预防或 避免酒精对胎儿发育的负面影响。表观遗传编程在人类进化过程中的作用 与酒精相关的表型将通过以下具体目标来解决： K1.为探讨孕期酒精暴露对胚胎头面部发育的影响： K2.评估基因变异对颅面发育的影响。 R1。妊娠酒精暴露对胎儿头面部基因表达变化的影响 R2。探讨母亲饮酒对产后颅面发育的纵向影响 R3.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有1800多名全职教职员工 38个部门，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排名第六。 《美国新闻与世界报道》跻身同行之列。

Project Summary 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 (ie. 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.