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

描述（申请人提供）：唇腭裂（CLP）是人类最常见的先天性畸形之一。它的高发病率和长期的多学科管理方案给世界各地的卫生保健系统带来了相当大的负担，并给患者及其家属带来了重大的心理和经济负担。CLP被认为是遗传易感性和妊娠第6周不利环境条件共同作用的结果。尽管在识别与CLP表现相关的基因方面取得了很大进展，但对于它们如何协调正常的唇腭裂发育仍然知之甚少。本研究旨在以鸡胚为模型系统，了解细胞粘附蛋白小家族——连接蛋白在正常唇腭裂形成过程中的作用。我们还将描述这些连接的缺陷所干扰的细胞过程，我们假设这些连接会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基因技术来专门调节卵细胞和面部外植体培养中融合前口面部上皮中的靶基因表达，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，并为分析连接蛋白在面部形态发生和CLP易感性中的功能提供有力的工具。公共卫生相关性：大约每600名儿童中就有一名出生时患有唇腭裂（上唇和下腭骨的开口或缺口），承受着大量的身体康复以及心理和经济成本。尽管它的影响，相对知之甚少的贡献因素，遗传和环境，使胎儿易患这种畸形。我们的研究将首次揭示受影响个体的发育机制受到干扰，从而最终有助于未来旨在减少面部唇裂发生率的研究。

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.