ORAL CLEFT PATHOGENESIS IN A MUTANT MOUSE MODEL

本研究的长期目标是了解颅面发育的分子遗传机制和口面裂的发病机制。包括唇裂和腭裂在内的口面裂是一种常见的出生缺陷，全世界每700个活产婴儿中就有1个受到影响。患有面部裂的人需要接受广泛的手术、牙科、语言和心理治疗，通常从婴儿期到青少年时期持续多年。尽管这种出生缺陷的发生频率和广泛的医学治疗相关，但导致唇裂和/或腭裂的原因和致病过程尚不清楚。本研究项目确定了一种独特的动物模型，用于研究唇腭裂的病因和发病机制。小鼠纯合子为自发的

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.