ORAL CLEFT PATHOGENESIS IN A MUTANT MOUSE MODEL

这项研究的长期目标是了解颅面发育和口裂发病的分子遗传学机制。口腔裂，包括唇裂和腭裂，是一种常见的出生缺陷，全世界大约每700名活产儿中就有1名受到影响。面裂患者需要接受广泛的外科、牙科、言语和心理治疗，这些治疗通常持续多年，从婴儿期一直持续到青少年。尽管这类出生缺陷经常发生和广泛的医学治疗，但导致唇裂和/或腭裂的原因和致病过程尚不清楚。本研究为研究口腔裂隙的病因和发病机制提供了一种独特的动物模型。纯合子小鼠为自发性 变种，舞者，表现出唇裂和腭裂。舞蹈家杂合子小鼠表现出易发生唇裂的倾向：这些突变小鼠在与不同的遗传背景杂交后出现唇裂，它们也显示出显着增加了对畸胎原诱导的唇裂的易感性。Dancer突变被定位在小鼠近端的19号染色体上，该染色体与人类染色体1lq13同线，这是一个与人类裂隙易感性有很强联系的区域。这项研究提出了三个具体目标：(1)全面评估Dancer突变小鼠IP/腭裂表型背后的致病发育过程；(2)分析Tbx22基因在人类X-连锁腭裂发育中的作用，并调查可能的遗传交互作用 (3)研究Dancer突变小鼠在裂隙发病过程中的基因-基因和基因-畸胎相互作用。这些研究将极大地提高我们对口腔裂隙形成的致病机制的了解，并将导致更好地诊断、治疗和/或预防口面部裂隙的方法的发展。

The long-term goal of the proposed research is to understand the molecular genetic mechanisms of craniofacial development and orofacial cleft pathogenesis. Orofacial clefts, including cleft lip and cleft palate, are common birth defects that affect approximately 1 in 700 live births worldwide. Individuals with facia clefts undergo extensive surgical, dental, speech and psychological therapies that usually last for many years from infancy through the teenage years. Despite the frequent occurrence and extensive medical treatment associated with such birth defects, the causes and the pathogenic processes that lead to cleft lip and/or cleft palate are not well understood. This research program has identified a unique animal model for studying the etiology and pathogenic mechanisms of orofacial clefting. Mice homozygous for a spontaneous mutation, Dancer, exhibit cleft lip and cleft palate. Dancer heterozygous mice show predisposition to clefting: these mutant mice show cleft lip after outcrossing to a different genetic background and they also exhibit significantly increased susceptibility to teratogen-induced clefting. The Dancer mutation is mapped to mouse proximal Chromosome 19, which is syntenic to human Chromosome 1lq13, a region with strong linkage to cleft susceptibility in humans. Three specific aims are proposed for this investigation: (1) To conduct a comprehensive evaluation of the pathogenic developmental processes underlying the cleft ip/palate phenotype in Dancer mutant mice; (2) To analyze the role of Tbx22, of which mutations cause X-linked cleft palate in humans, in craniofacial development and to investigate possible genetic interactions between Dancer and mutations in Tbxl and Tbx22 during cleft pathogenesis; (3) To characterize gene-gene and gene-teratogen interactions during cleft pathogenesis in Dancer mutant mice. These studies will greatly increase our understanding of the pathogenic mechanisms underlying orofacial cleft formation and will lead to development of methods for better diagnosis, treatment and/or prevention of orofacial clefting.