DNA Methylation in Orofacial Clefting

口颌面裂中的 DNA 甲基化

基本信息

批准号：
9374573
负责人：
Robert Lipinski
金额：
$ 14.82万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9374573
关键词：
Acute Address Affect Attenuated Biological Biological Process Candidate Disease Gene Cell Proliferation Cells Cellular Morphology Cephalic Child Cleft Palate Complex Congenital Abnormality DNA Methylation DNA Methylation Inhibition DNA Modification Methylases DNA analysis DNA methyltransferase inhibition Data Development Dietary Supplementation Embryo Environmental Risk Factor Epidemiology Epigenetic Process Epithelium Etiology Event Face Focus Groups Foundations Future Genes Genetic Genetic Recombination Genetic Transcription Genetic study Genome Goals Growth Health Care Costs Human In Vitro Individual Intervention Investigation Knowledge Life Link Mediating Mediator of activation protein Medical Mesenchymal Mesenchyme Methylation Modeling Molecular Morbidity - disease rate Morphogenesis Mus Neural Crest Neural Crest Cell Newborn Infant Operative Surgical Procedures Palate Pathogenesis Pathway interactions Penetrance Pharmacology Phenotype Population Population Process Prevention Prevention strategy Research Role Secondary Palate Structural Congenital Anomalies Surface Technology Testing Therapeutic Time base cleft lip and palate critical period gene environment interaction genome wide methylation genome-wide in vivo insight malformation methylome mortality novel orofacial cleft orofacial development palatal shelves peer prevent trait transcriptome transcriptome sequencing

项目摘要

Orofacial clefts (OFCs) of the lip and palate are common structural birth defects, affecting 1 in 700 newborns. These malformations cause significant morbidity, require extensive medical intervention, and pose serious individual, familial, and societal burdens. Children with OFCs undergo an average of six surgeries, have health care costs 800% greater than their peers, and have higher mortality rates at all stages of life. Prevention strategies for OFCs are elusive because our current understanding of causative factors is inadequate. Epidemiologic and traditional genetic studies have shown that OFCs are etiologically complex traits that likely result from gene-environment interactions. Epigenetic mechanisms are an exciting new focus in understanding the genesis of OFCs because they mediate the effect of environmental influences on the genome during sensitive embryonic periods. This application specifically focuses on DNA methylation because this epigenetic mechanism is environmentally sensitive and a practical target of prevention and therapeutic strategies. While implicated by multiple lines of evidence, the biological role of DNA methylation in orofacial development is not known. Moreover, while many molecular mediators of orofacial development have been identified, the specific genes and pathways that are regulated by DNA methylation during cleft pathogenesis have not been well defined. The studies proposed in this application utilize genetic and pharmacologic approaches to define the biological role of DNA methylation in orofacial development, and genome-wide integrative analysis of DNA methylation and transcriptional expression to identify candidate genes and pathways that are sensitive to changes in methylation. Completion of these Aims will advance the field by dramatically increasing our understanding of the basic mechanisms by which DNA methylation regulates orofacial development, and how modulation of this key epigenetic process results in OFCs. The results are expected to link this environmentally-sensitive mechanism to a distinct biological process and cell population, and identify a focused group of epigenetically-regulated and environmentally-sensitive targets. This will provide a foundation for future focused research efforts that will advance our long term goal of developing prevention strategies for etiologically complex birth defects.

嘴唇和口感的口面裂（OFC）是常见的结构性先天缺陷，影响了700名新生儿中的1个。这些畸形会导致明显的发病率，需要广泛的医疗干预，并严重个人，家族和社会负担。 OFC的儿童平均进行六项手术，健康护理费用比同龄人高800％，并且在生活的各个阶段的死亡率更高。预防 OFC的策略难以捉摸，因为我们目前对因果因素的理解不足。流行病学和传统遗传研究表明，OFC是病因学上的复杂特征基因环境相互作用产生。表观遗传机制是令人兴奋的新焦点了解OFC的起源，因为它们介导了环境影响对基因组的影响在敏感的胚胎时期。该应用专门针对DNA甲基化，因为这表观遗传机制对环境敏感，是预防和治疗的实用目标策略。虽然由多种证据与DNA甲基化的生物学作用有关发展尚不清楚。此外，尽管许多分子介质已经鉴定出在裂口发病机理期间受DNA甲基化调节的特定基因和途径尚未得到很好的定义。该应用中提出的研究利用遗传学和药理定义DNA甲基化在口面发育和全基因组中的生物学作用的方法 DNA甲基化和转录表达的综合分析，以鉴定候选基因和对甲基化变化敏感的途径。这些目标的完成将通过大大提高了我们对DNA甲基化调节的基本机制的理解口面发育以及该关键表观遗传过程的调节如何导致OFC。结果是有望将这种对环境敏感的机制与独特的生物过程和细胞种群联系起来，并确定一组专注的表观遗传调节和对环境敏感的靶标。这会为未来的专注研究工作提供基础，这将促进我们发展的长期目标病因复杂的先天缺陷的预防策略。