GENE DISCOVERY FOR CRANIOFACIAL DISORDERS

出生缺陷影响美国约5%的atl婴儿，四分之三涉及头部，面部和口腔组织。的 最常见的颅面出生缺陷是口面裂：唇裂+/-唇腭裂（CUP）影响约1/1100 在美国，每1600名新生儿中就有一例腭裂。因此，口面裂代表了相当多的公众 健康问题和费用，大多数病例现在无法预测或预防。孤立， “非综合征型”CL/P（nsCb 'P）是最常见的颅面出生缺陷，占所有先天性畸形的约70%。 nsCLtP是一种非孟德尔的多因素疾病，由多个基因引起，每个基因都发挥作用。 相对较小的影响，相互作用并与环境因素相互作用，最终导致 胎儿颅面发育过程中特定通路和遗传网络的缺陷作用。然而，在这方面， 目前已知的导致nsCL/P的基因很少，环境影响也没有 肯定的该提案的目标是确定基因，途径和遗传网络， 参与颅面发育，因此代表了遗传和非遗传的潜在目标， nsCL/P的决定因素。确定这些目标将是必要的，以制定治疗策略 最终目的是防止这种使人衰弱和毁容的出生缺陷。 准确研究人类颅面发育过程中的基因作用目前是非常困难的。 因此，我们计划在发展中国家的基因表达谱进行仔细的微阵列研究。 小鼠，其中遗传背景（C57 BL/6 J），仔细定时胎龄，在许多 时间点和许多重复样品的分析都可以很容易地实现，此外，我们计划 在Ski基因座的无效敲除等位基因的纯合子小鼠中进行的面部发育的类似研究， C57 BL/6 J的背景。这些Ski -/-小鼠有极高的中线面部裂缝率， 提供了异常颅面发育过程中基因表达的宝贵比较， 特别是，应确定响应Ski的发育相的遗传途径和网络。 对于在面部发育过程中显得特别重要的基因，我们将识别和验证人类 SNPs用于未来nsCL/P的连锁和关联研究。我们将应用最先进的生物信息学 分析和解释数据的工具，我们将所有这些数据存款适当的公共数据存储库。

Birth defects affect -5% of atl infants in the USA, three-fourths involving the head, face, and oral tissues. The most frequent craniofacial birth defects are orofacial clefts: cleft lip +/- cleft paiate (CUP) affects ~1 per 1100 births in the USA, and cleft palate ~1 per 1600 births. Orofacial clefts thus represent a considerable public health problem and expense, and most cases cannot now be predicted or prevented. Isolated, "non-syndromic" CL/P (nsCb'P) is the most common craniofacial birth defect, accounting for -70% of all cases of CL/P. nsCLtP is a non-Mendelian, multifactorial disorder, due to multiple genes, each exerting a relatively small effect, interacting with each other and with environmental factors to ultimately result in defective action of specific pathways and genetic networks during fetal craniofacial development. However, few of the genes, and none of the environmental influences, that contribute to nsCL/P are currently known with certainty. The goal of this proposal is to identify the genes, pathways, and genetic networks that are involved in craniofacial development and that thus represent potential targets for genetic and non-genetic determinants of nsCL/P. Identification of these targets will be necessary to devise therapeutic strategies ultimately aimed at preventing this debilitating and disfiguring birth defect. It is currently very difficult to accurately study gene action during craniofacial development in the human. Accordingly, we plan a careful microarray study of gene expression profiles in the developing face of the mouse, in which genetic background (C57BL/6J), careful timing of fetal age, sampling at numerous timepoints, and analyses of many replicate samples can all be readily achieved, in addition, we plan an analogous study of facial development in mice homozygous for a null knockout allele of the Ski locus, carried on the C57BL/6J background. These Ski -/- mice have an exceedingly high rate of midline facial clefts, providing an invaluable comparison of gene expression during aberrant craniofacial development that, in particular, should identify genetic pathways and networks of the developing facies that are responsive to Ski. For genes that appear of particular importance during facial development, we will identify and validate human SNPs for use in future linkage and association studies of nsCL/P. We will apply state-of-art bioinformatics tools to analyze and interpret the data, ali of which we will deposit in appropriate public data repositories.