The role of Nectins in fusion of the midface and genesis of cleft lip and palate.

Nectins 在中面部融合以及唇裂和腭裂发生中的作用。

基本信息

批准号：
8205018
负责人：
Timothy Chilton Cox
金额：
$ 47.78万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2013-03-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8205018
关键词：
19q13.3 3q13 Affect Antibodies Behavior Biological Models Cell Adhesion Molecules Cell Maintenance Cell physiology Cells Chick Embryo Child Chinese People Cleaved cell Clinical Complex Congenital Abnormality Cytoplasmic Tail Deformity Development Dominant-Negative Mutation Ectodermal Dysplasia Ectopic Expression Embryo Epithelial Epithelial Cells Epithelium Etiology Face Family Fetus Financial cost Future GTP-Binding Proteins Gene Expression Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Head Health Healthcare Systems Human Immunoglobulins Incidence Individual Integral Membrane Protein Lasers Light Link Lip structure Messenger RNA Methodology Molecular Morphogenesis Mus Mutation Opitz syndrome Optics PTPN11 gene PVRL1 Palate Pathogenesis Pathway interactions Patients Phosphoric Monoester Hydrolases Play Population Predisposition Pregnancy Premaxillary palate Process Protein Isoforms Proteins Protocols documentation RNA Splicing Rehabilitation therapy Relative (related person)Reproducibility Research Role Secondary Palate Shapes Signal Transduction Syndrome Techniques Tissues Transfection Transmission Electron Microscopy Van der Woude syndrome X-Ray Computed Tomography cell behavior cleft lip and palate cohort craniofacial genetic technology genome wide association study imaging modality immunocytochemistry in utero malformation man member multidisciplinary nectin novel orofacial palatal fusion psychologic reconstruction tomography tool

项目摘要

DESCRIPTION (provided by applicant): Cleft lip and palate (CLP) is one of the most common congenital malformations in humans. Its high incidence and prolonged multidisciplinary management protocols place considerable burden on health care systems worldwide, and significant psychological and financial burden on patients and their families. CLP is thought to arise as a result of the combination of both a genetic susceptibility and adverse environmental conditions in the sixth week of gestation. Although much progress has been made in identifying genes associated with the presentation of CLP, there is still relatively little known about how they all function to orchestrate normal lip and palate development. This proposal aims to understand the role of a small family of cell adhesion proteins, the nectins, in the normal process of lip and palate formation using the chick embryo as the model system. We will also delineate the cellular processes perturbed by deficiencies of these nectins that we hypothesize predisposes the developing fetus to CLP. To achieve this, we will utilize a variety of powerful new genetic technologies developed to specifically modulate target gene expression in pre-fusion orofacial epithelia in ovo and in facial explant cultures, with phenotypic consequences quantitatively assessed using different multidimensional imaging modalities. These approaches should overcome some of the limitations that have hindered progress in this field and provide a powerful tool in the analysis of nectin function in facial morphogenesis and the predisposition to CLP. PUBLIC HEALTH RELEVANCE: Around one in 600 children are born with cleft lip and palate (an opening or gap in the upper lip and underlying bony palate) and burdened with the extensive physical rehabilitation as well as psychological and financial cost. Despite its impact, relatively little known about the contributing factors, both genetic and environmental, that predispose the fetus to this deformity. Our studies will shed some of the first light on the developmental mechanisms that are perturbed in affected individuals and thus ultimately aid future studies aimed at reducing the incidence of facial clefts.

描述（由申请人提供）：唇腭裂（CLP）是人类最常见的先天畸形之一。其高发病率和长期的多学科管理方案给全世界的医疗保健系统带来了相当大的负担，也给患者及其家人带来了巨大的心理和经济负担。 CLP被认为是遗传易感性和妊娠第六周不利环境条件共同作用的结果。尽管在鉴定与 CLP 表达相关的基因方面已经取得了很大进展，但人们对它们如何协调正常唇部和上颚发育的功能仍知之甚少。该提案旨在以鸡胚胎为模型系统，了解细胞粘附蛋白小家族（Nectin）在唇部和腭形成正常过程中的作用。我们还将描述因这些 nectin 缺陷而受到干扰的细胞过程，我们假设这些 nectin 使发育中的胎儿易患 CLP。为了实现这一目标，我们将利用各种强大的新遗传技术来专门调节卵内融合前口面部上皮和面部外植体培养物中的靶基因表达，并使用不同的多维成像方式定量评估表型后果。这些方法应该克服阻碍该领域进展的一些限制，并为分析面部形态发生中的 nectin 功能和 CLP 倾向提供强大的工具。公共健康相关性：大约六百名儿童中就有一人患有唇腭裂（上唇和下方骨腭的开口或间隙），并承受着广泛的身体康复以及心理和经济成本。尽管有其影响，但人们对导致胎儿易患这种畸形的遗传因素和环境因素知之甚少。我们的研究将首次揭示受影响个体中受到干扰的发育机制，从而最终帮助旨在减少面部裂痕发生率的未来研究。