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。它的高发病率和长时间的多学科管理方案给世界各地的医疗保健系统带来了相当大的负担，给患者及其家人带来了巨大的心理和经济负担。CLP被认为是在怀孕第六周时遗传易感性和不利环境条件共同作用的结果。尽管在识别与CLP相关的基因方面已经取得了很大进展，但对于它们如何协调正常的唇腭部发育仍然知之甚少。这项建议旨在以鸡胚胎为模型系统，了解细胞黏附蛋白小家族--蜜腺蛋白在唇腭部正常形成过程中的作用。我们还将描述因这些蜜腺蛋白的缺乏而受到干扰的细胞过程，我们假设这些缺陷使发育中的胎儿容易患上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融合前的口腔面部上皮细胞和面部外植体培养中的靶基因表达，并使用不同的多维成像模式对表型结果进行定量评估。这些方法应该可以克服阻碍这一领域进展的一些局限性，并为分析面部形态发生和CLP易感性中的Nextin功能提供一个强有力的工具。与公共卫生相关：大约每600名儿童中就有一名出生时患有唇腭裂(上嘴唇和下面的骨腭部的开口或缺口)，并承担着广泛的身体康复以及心理和经济成本。尽管它的影响，但相对鲜为人知的促成因素，包括遗传和环境，使胎儿倾向于这种畸形。我们的研究将对受影响的个体的发育机制提供一些初步的了解，从而最终有助于未来旨在减少面部裂隙发生率的研究。

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.