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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.

唇腭裂是一种常见的结构性出生缺陷，每700个新生儿中就有1个患有此病。