GENE DISCOVERY FOR CRANIOFACIAL DISORDERS

在美国，出生缺陷影响-5%的ATL婴儿，四分之三涉及头部、面部和口腔组织。这个 最常见的头面部出生缺陷是口面部裂：唇裂+/-唇裂(CUP)影响每1100人中约1人 在美国出生的婴儿，每1600名新生儿中就有1名患有腭裂。因此，口腔裂隙代表了相当多的公众 健康问题和费用，现在大多数病例是无法预测或预防的。与世隔绝， 非综合征型CL/P(nsCb‘P)是最常见的头面部出生缺陷，占出生缺陷的-70% CL/P的病例nsCLtP是一种非孟德尔式的多因素疾病，由于多个基因，每个基因都施加一种 影响相对较小，相互作用，与环境因素相互作用，最终导致 胎儿头面部发育过程中特定通路和遗传网络的作用缺陷。然而， 目前已知的影响nsCL/P的基因很少，也不存在环境影响 肯定会的。这项建议的目标是确定基因、途径和遗传网络 参与颅面发育，因此是遗传性和非遗传性的潜在靶点 NsCL/P的决定因素确定这些靶点对于制定治疗策略是必要的 最终目的是防止这种令人衰弱和毁容的出生缺陷。 目前，准确研究人类头面部发育过程中的基因活动是非常困难的。 因此，我们计划对发育中的人的基因表达谱进行仔细的微阵列研究 小鼠，其中遗传背景(C57BL/6J)，仔细计时胎龄，多次取样 时间点，以及对许多重复样本的分析都可以很容易地实现，此外，我们计划 滑雪基因缺失敲除等位基因纯合子小鼠面部发育的类似研究 以C57BL/6J为背景。这些滑雪鼠的正中线面部裂纹率非常高， 提供了异常颅面发育过程中基因表达的宝贵比较，在 特别是，应确定对滑雪作出反应的发育相的遗传路径和网络。 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 用于未来nsCL/P连锁和关联研究的SNPs。我们将应用最先进的生物信息学 分析和解释数据的工具，我们将把这些数据存放在适当的公共数据存储库中。

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.