Using Frog Faces to Better Understand Clefts in the Primary Palate

描述（由申请人提供）：大多数关于面部的研究集中在次腭上，而对主腭的了解相对较少。因此，该实验室的广泛目标是填补该领域的这一重大知识空白，并进一步了解有关该结构的初级腭形成和缺陷，如正中口面裂。要做到这一点，我们已经开发了一个创新的模型系统，使用非洲爪蟾研究orofacial发展。我们已经发现了新的作用，视黄酸信号在调节生长和收敛的面部神经元在这个物种是保守的哺乳动物。此外，在发育的特定时间扰乱这一信号通路，会导致与人类正中面裂非常相似的初级腭裂。这种面部裂缝虽然罕见，但也与许多人类综合症有关。此外，小干扰的发展，初级腭已被假定为一个潜在的原因，裂缝的次级腭。因此，我们对初级腭发育的研究可能对人类面裂的治疗干预和预防的发展产生重大影响。我们已发表的和初步的研究促使我们形成这样的假设，即视黄酸信号调节同源框基因、表观遗传调节剂和细胞周期调节剂，这些基因会聚在一起最终控制形成初级腭的面部组织的细胞增殖。我们在目标1和2中测试了这一假设，其中我们结合了联合收割机现代分子测定和经典胚胎学，特别是利用面部移植和形态测量分析。由于口面发育是复杂的，许多因素可能导致出生缺陷，在这一地区，更好地了解如何初级腭发展是至关重要的。此外，识别能够影响内源性发育途径的环境毒素也很重要。在目标3中，我们建议使用化学筛选作为一种无偏见的方法来发现初级腭发育的新机制，并测试环境毒素是否会加剧正中裂。

DESCRIPTION (provided by applicant): Most research concerning the face focuses on the secondary palate, while relatively less is known about the primary palate. Therefore, the broad goals of the lab are to fill this significant knowledge gap in the field and further our understanding of primary palate formation and defects concerning this structure such as median orofacial clefts. To do so we have developed an innovative model system using Xenopus laevis to study orofacial development. We have uncovered novel roles for retinoic acid signaling in regulating growth and convergence of the facial prominences in this species that are conserved in mammals. Moreover, perturbing this signaling pathway, at a specific time in development, results in a cleft in the primary palate that closely resembles human median facial clefts. Such facial clefts while rare, are also associated with a number of human syndromes. Moreover, small disturbances in the development of the primary palate have been postulated to be an underlying cause of clefts in the secondary palate. Therefore, our studies of primary palate development could have significant impact on the development of therapeutic interventions and prevention of facial clefts in humans. Our published and preliminary studies have prompted us to form the hypothesis that retinoic acid signaling regulates homeobox genes, epigenetic modulators and cell cycle regulators that converge to ultimately control cell proliferation of the facial tissues that form the primary palate. We test this hypothesis in aims 1 and 2 where we combine modern molecular assays and classical embryology, notably utilizing face transplants and morphometric analyses. Since orofacial development is complex and many factors can contribute birth defects in this region a better understanding of how the primary palate develops is critical. In addition, it is also essential to identify environmental toxins that can influence he endogenous developmental pathways. In the aim 3 we propose to use chemical screens as an unbiased method to find novel mechanisms in primary palate development and to test whether environmental toxins can exacerbate median clefts.