Maternal alcohol exposure: impact on genetic control of craniofacial phenotype

母亲酒精暴露：对颅面表型遗传控制的影响

• 批准号: 8189779
• 负责人: Ali Murat Maga
• 金额: $ 12.5万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8189779
• 关键词: Address; Adult; Adverse effects; Affect; Alcohol consumption; Alcohols; Animal Model; Award; Backcrossings; Bioinformatics; Chromosome Mapping; Chronic; Clinical Research; Communities; Confounding Factors (Epidemiology); Consumption; DNA Methylation; Data; Dentistry; Development; Developmental Gene; Diagnosis; Diagnostic; Disease; Dose; Dysmorphology; Embryo; Embryology; Environment; Environmental Risk Factor; Epigenetic Process; Ethanol; Event; Exposure to; Face; Faculty; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Fetal Development; Fetus; Future; Gender; Gene Expression; Gene-Modified; Genes; Genetic; Genetic Variation; Genomics; Goals; Growth; Health; Human; Image; Imaging Techniques; Lead; Location; Long-Term Effects; Malnutrition; Maps; Maternal Age; Measurable; Mediating; Medicine; Methodology; Methods; Mind; Modeling; Modification; Molecular; Molecular Profiling; Morphogenesis; Morphology; Mouse Strains; Mus; Optics; Outcome; Pathway interactions; Perinatal Exposure; Phase; Phenotype; Postdoctoral Fellow; Pregnancy; Quantitative Genetics; Quantitative Trait Loci; Race; Reporting; Research; Research Infrastructure; Research Personnel; Resolution; Role; Science; Shapes; Skeleton; Stress; Techniques; Testing; Time; Translating; Uncertainty; Universities; Variant; Washington; alcohol effect; alcohol exposure; alcohol response; base; clinical practice; craniofacial; digital imaging; dosage; fetal; fetal programming; improved; in utero; in vivo; interest; malformation; medical schools; member; mouse development; mouse model; news; novel; offspring; pediatric department; peer; pre-clinical; prevent; programs; response; skeletal; skills; tomography; tool; trait; web interface

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.

描述（由申请人提供）：我是西雅图的华盛顿大学儿科颅面医学部的博士后研究员。我的研究兴趣在于了解机制（即基因和环境因素的贡献）负责人类畸形，特别是颅面疾病，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测量学作为一种手段，定量评估颅面表型。我申请这个K99/R 00独立之路奖的长期目标是成为颅面畸形学领域的独立研究人员。我已经开发了一个研究计划，以增加我在定量形态学和3D数字成像与定量遗传学和胚胎学的背景，使自己成为生物医学科学的独立研究者。作为实现这一目标的第一步，我将探索妊娠期酒精暴露对小鼠胚胎和出生后颅面发育的影响：（1）最先进的高分辨率体内microCT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，和（3）使用中等剂量慢性乙醇暴露的新型小鼠模型，其在成人中产生FAS相关的可测量表型。该提议的长期目标是（1）通过详细定量颅面表型来研究表观遗传编程在呈现酒精相关畸形中的作用，和（2）将基因组差异与这些特征相关联，以找到表观遗传修饰的基因，从而导致表型差异。在未来，这些基因及其在该模型中修饰的机制可以转化为临床研究，并有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这些具体目标来解决：K1。探讨妊娠期酒精暴露对胚胎颅面发育的影响。评估遗传变异对颅面发育的影响。R1描述胎儿颅面基因表达变化对妊娠期乙醇暴露的反应。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，以提供本提案的数据和结果。华盛顿大学医学院和牙科学院在38个系有1,800多名全职教师，其中包括8名诺贝尔奖获得者。今年，华盛顿大学儿科系在《美国新闻与世界报道》的同行中排名第六。 公共卫生关系：胎儿酒精综合征是母亲饮酒的最极端后果，具有相当大的健康重要性。胎儿暴露于乙醇导致高度可变结局的原因尚不清楚。这种不确定性可能与乙醇暴露的剂量、时间和持续时间以及种族、性别和母亲年龄的影响有关。了解影响颅面形态的因素是改善胎儿酒精谱系障碍的诊断和管理的重要步骤，并将显着帮助制定更有效的教育计划，有关母亲饮酒对胎儿和成人健康的不利影响。将使用独特的动物模型并严格控制混杂变量（如环境、剂量和遗传学）来探索这些因素。