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：
7738522
负责人：
Timothy Chilton Cox
金额：
$ 29.69万
依托单位：
UNIVERSITY OF WASHINGTON
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 2010-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7738522
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 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 public health relevance 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）：唇裂（CLP）是人类最常见的先天性畸形之一。它的高发病率和延长的多学科管理方案给全球卫生保健系统带来了巨大负担，并给患者及其家人带来了巨大的心理和经济负担。人们认为CLP是由于妊娠第六周在遗传敏感性和不利环境条件下的结合而产生的。尽管在识别与CLP的呈现相关的基因方面取得了很多进展，但对于它们如何运作正常的嘴唇和口感发育，仍然相对较少。该建议旨在了解小家族的细胞粘附蛋白（蜜蜂）在使用雏鸡胚胎作为模型系统的正常过程中的作用。我们还将描绘出这些蜜饯的缺乏扰动的细胞过程，我们假设我们倾向于发育中的胎儿对CLP。为了实现这一目标，我们将利用各种开发的强大的新遗传技术来特异性地调节OVO和面部膨胀培养物中的融合前类似上皮细胞中的靶基因表达，并使用不同的多维成像模式进行了定量评估的表型后果。这些方法应克服一些阻碍该领域进展的局限性，并在分析面部形态发生和CLP的倾向中为nectin功能提供了强大的工具。公共卫生相关性：大约有600名儿童出生时有嘴唇和口感（上唇的开口或差距和底层骨质口感），并承受着广泛的身体康复以及心理和经济成本的负担。尽管有影响，但对遗传和环境的促成因素的了解鲜为人知，这些因素使胎儿易于这种畸形。我们的研究将对受影响的个体受到干扰的发展机制进行一些阐述，从而最终有助于未来的研究，旨在减少面部裂缝的发生率。