Molecular and cellular mechanisms causing cleft lip/palate

项目摘要 唇裂伴或不伴腭裂(CLP)是男性最常见的出生缺陷之一，其发病率为 全世界每700到1000名活产儿中就有1人死亡。在过去的几年里，已经取得了相当大的进展 几十年来确定CLP综合征形式的基因和全基因组相关性研究 涉及到许多基因组区域(和候选基因)对非综合征的遗传贡献 中电。然而，对于很大一部分唇裂病例来说，潜在的遗传基础仍然未知。在……里面 此外，对裂解基因功能的大部分关注都集中在少数转录调节因子和生长上。 被牵连的因素，很大程度上忽略了许多其他致病基因。我们寻求新的发现 来自两个已知的CLP蛋白，IRF6和MID1，这表明功能围绕着直接 唇部形态发生过程中上皮细胞-细胞黏附的调控。该项目调查了新的 发现这些蛋白质中的每一种都与负责协调动态的过程有联系 细胞间黏附复合体的行为与细胞骨架的潜在变化 最终促进嘴唇的形态发生。此外，我们还进一步支持 通过研究可能的致病原的直接功能影响来研究这一特定调控复合体的组成部分 最近在一组患有非综合征性CLP的多代大家系中发现了变异。这个 该项目的亮点不仅仅是对CLP背后的分子机制的独特洞察， 研究计划提供了各种新颖和最先进的方法来进行有针对性的工作 了解这种常见出生缺陷的原因。

Project Summary Cleft lip with or without cleft palate (CLP) is one of the most common birth defects in man with an incidence of between 1 in 700 and 1 in 1000 live births worldwide. Considerable progress has been made over the last few decades to determine the genes responsible for syndromic forms of CLP and genome-wide association studies have implicated many genomic regions (and candidate genes) in the genetic contribution to non-syndromic CLP. However, for a substantial fraction of cleft cases, the underlying genetic basis remains unknown. In addition, much of the focus on cleft gene functions has been on the few transcriptional regulators and growth factors that have been implicated, largely ignoring the many other causative genes. He we pursue new findings from two known CLP proteins, IRF6 and MID1, that suggest a convergence of function around the direct regulation of epithelial cell-cell adhesion during lip morphogenesis. The project investigates the newly discovered linkages that each of these proteins have with processes responsible for coordinating the dynamic behavior of intercellular adhesion complexes with the underlying changes in the cellular cytoskeleton that ultimately facilitate morphogenesis of the lip. In addition, we provide further support for the importance of components of this specific regulatory complex by investigating the direct functional impact of likely pathogenic variants recently discovered in a cohort of large multigenerational families with non-syndromic CLP. The project is highlighted not just by the unique insight into the molecular mechanisms underlying CLP that the research plan offers, but also the various novel and state-of-the-art approaches used to pursue the work aimed at understanding the causes of this common birth defect.