GENE DISCOVERY FOR CRANIOFACIAL DISORDERS

描述（由申请人提供）：出生缺陷影响美国约5%的婴儿，其中四分之三涉及头部，面部和口腔组织。最常见的颅面出生缺陷是口面裂：在美国，唇裂+/-腭裂（CL/P）约为1/1100，腭裂约为1/1600。因此，口面裂是一个相当大的公共卫生问题和费用，大多数病例现在无法预测或预防。孤立的“非综合征”CL/P（nsCL/P）是最常见的颅面出生缺陷，约占所有CL/P病例的70%。nsCL/P是一种非孟德尔的多因素疾病，由于多个基因，每个基因的影响相对较小，相互作用，并与环境因素，最终导致有缺陷的行动，具体途径和遗传网络在胎儿颅面发展然而，很少的基因，没有一个环境的影响，有助于nsCL/P是目前已知的确定性。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，从而代表潜在的目标，遗传和非遗传决定因素的nsCL/P。这些目标的识别将是必要的，以制定治疗策略，最终旨在防止这种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，我们计划一个仔细的基因表达谱的微阵列研究在发展中国家面临的小鼠，其中遗传背景（C57 BL/6 J），仔细定时胎龄，在许多时间点采样，并分析了许多重复样品都可以很容易地实现。此外，我们计划在C57 BL/6 J背景上进行的Ski基因座的无效敲除等位基因纯合子小鼠中进行类似的面部发育研究。这些Ski -/-小鼠具有极高的中线面裂率，提供了异常颅面发育期间基因表达的宝贵比较，特别是应该确定对Ski有反应的发育中的面部的遗传途径和网络。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SNP，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工具来分析和解释数据，所有这些数据我们都将存款适当的公共数据库。

DESCRIPTION (provided by applicant): Birth defects affect approximately 5% of all 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 palate (CL/P) 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 (nsCL/P) is the most common craniofacial birth defect, accounting for approximately 70% of all cases of CL/P. nsCL/P 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, all of which we will deposit in appropriate public data repositories.