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

描述（由申请人提供）：唇腭裂（CLP）是人类最常见的先天性畸形之一。其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六周不利环境条件共同作用的结果。虽然在识别与CLP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唇和腭发育的功能仍然知之甚少。本研究以鸡胚为模型系统，探讨细胞粘附蛋白nectin家族在唇腭形成过程中的作用。我们还将描绘这些nectin的缺陷，我们假设易患CLP发育中的胎儿扰乱的细胞过程。为了实现这一目标，我们将利用各种强大的新的遗传技术，专门调制目标基因的表达融合前口面上皮细胞在卵和面部外植体培养，与表型的后果定量评估使用不同的多维成像模式。这些方法应该克服一些限制，阻碍了在这一领域的进展，并提供了一个强大的工具，在面部形态发生和CLP的易感性的nectin功能的分析。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（上唇和下面的骨性腭的开口或间隙），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，相对鲜为人知的贡献因素，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，从而最终有助于未来旨在减少面部裂缝发生率的研究。

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.