ORAL CLEFT PATHOGENESIS IN A MUTANT MOUSE MODEL

该研究的长期目标是了解颅面发育和口面裂发病机制的分子遗传机制。口面裂，包括唇裂和腭裂，是常见的出生缺陷，影响全球约1/700的活产。患有面部裂的人要接受广泛的手术、牙科、语言和心理治疗，这些治疗通常从婴儿期到青少年时期持续多年。尽管与此类出生缺陷相关的频繁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。这项研究计划已经确定了一个独特的动物模型，研究的病因和发病机制的口面裂。小鼠纯合子自发 突变体丹瑟表现出唇腭裂Dancer杂合子小鼠表现出易裂倾向：这些突变小鼠在与不同遗传背景异交后表现出唇裂，并且它们还表现出对致畸剂诱导的裂的易感性显著增加。Dancer突变定位于小鼠近端19号染色体，该染色体与人类染色体1 lq 13同线，该区域与人类的裂缝易感性有很强的连锁关系。本研究提出了三个具体目标：（1）对Dancer突变小鼠中ip/palate表型的致病性发育过程进行全面评估;（2）分析Tbx 22在颅面发育中的作用，其中Tbx 22突变导致人类X连锁腭裂，并研究Tbx 22突变与颅面发育之间可能的遗传相互作用。 Dancer与Tbx 1和Tbx 22突变的关系;（3）研究Dancer突变小鼠唇腭裂发病过程中基因-基因和基因-致畸因子的相互作用。这些研究将大大增加我们对口面裂形成的致病机制的理解，并将导致更好地诊断，治疗和/或预防口面裂的方法的发展。

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.