Studies on the pathogenesis of CHARGE syndrome

CHARGE综合征是一种常染色体显性遗传畸形综合征。据推测，在CHARGE综合征患者中观察到的大多数特征是由于神经嵴发育异常。通过对野生型和Chd7缺陷小鼠胚胎（第9.5天）进行全基因组微阵列表达分析，我们可以鉴定出许多Chd7靶基因，这些基因在神经嵴细胞发育和迁移中具有功能。因此，在这里提出的建议的目标是在Chd7缺陷的神经嵴细胞的分子病理机制的分析和监管网络的识别。确定调控网络，CHD7调控的关键基因及其特异性校正可能是建立治疗方案的重要方面。我们已经对CHD7调节的化学引诱物分子Sema3a进行了功能分析。这些研究导致假设Sema3a在CHARGE综合征的发病机制中起修饰剂的作用。因此，我们想通过对携带CHD7突变的轻度和重度CHARGE综合征患者进行小鼠胚胎实验、细胞培养研究和SEMA3A突变筛查来阐明这一假设。

CHARGE syndrome is an autosomal dominant malformation syndrome. It was postulated, that most features seen in CHARGE syndrome patients are due to abnormalities in neural crest development. By performing a genome-wide microarray expression analysis on wild-type and Chd7 deficient mouse embryos (at day 9.5) we could identify many Chd7 target genes, with functions in neural crest cell development and migration. Therefore, objectives in the here presented proposal are the analysis of the molecular pathomechanisms in Chd7 deficient neural crest cells and the identification of regulatory networks. The identification of regulatory networks, CHD7 regulated key genes and their specific correction could be important aspects for the establishment of therapeutic options. We already performed functional analysis for the CHD7 regulated chemoattractant molecule Sema3a. These studies lead to the hypothesis that Sema3a act as a modifier in the pathogenesis of CHARGE syndrome. Therefore, we would like to clarify this hypothesis by performing experiments on mouse embryos, cell culture studies and a SEMA3A mutational screening in mild and severely affected CHARGE syndrome patients carrying a CHD7 mutation.