Characterization of a novel Drosophila disease model for CHARGE Syndrome

描述（由申请人提供）：CHARGE综合征（CS）是一种罕见的常染色体显性遗传疾病，其特征为多种临床症状。其中最常见的包括缺损、后鼻孔闭锁、半规管异常、心脏缺陷、智力迟钝、生长迟缓以及生殖器和耳部异常，使得CS成为先天性异常的常见原因。它在每10，000名活产婴儿中约有1人中普遍存在，很大程度上是由人类Chd 7基因功能缺失突变（Chd 7单倍不足）引起的。Chd 7的突变占所有诊断为CS的患者的约2/3，尽管对该蛋白质调节的基因（和细胞过程）知之甚少。该项目的长期目标是通过表征和应用一种新的果蝇疾病模型，更深入地了解CS的发病机制。我们的希望是，这里提出的研究将最终导致新的诊断工具和/或治疗CS患者的治疗目标。 通过对模式生物的研究，对许多人类疾病复杂病因学的理解得到了改善。果蝇（Drosophila melanogaster）在促进我们对各种人类疾病机制的理解方面具有非常重要和影响力。使用RNA干扰（RNAi）基因敲低策略，我们已经创建了第一个果蝇模型CS在成年苍蝇。因为kis及其人类同源物Chd 7编码转录因子，所以鉴定其表达受这些转录因子调节并且其功能也有助于疾病病理学的生物学相关靶基因对于更好地理解这种疾病的发病机理以及更好地合理设计治疗干预和/或诊断和预后指标将是至关重要的。果蝇作为模式生物，在基因发现和功能基因分析方面有着无可比拟的作用。在果蝇中使用遗传筛选和微阵列分析，我们已经确定了一些靶基因的表达调控的kis功能。这些靶基因中的许多具有促进疾病病理学的一个或多个方面的潜力。我们希望通过以下具体目标进一步测试我们已经确定的哪些基因可能有助于CS中疾病病理学的特定方面：采用遗传学，行为学和细胞生物学方法进一步表征哪些Kismet靶基因可能与CS中观察到的疾病症状生物学相关。我们将特别关注我们的分析在粗大运动功能障碍，智力残疾，和神经元形态的缺陷。 公共卫生相关性：果蝇（Drosophila melanogaster）在促进我们对各种人类疾病（包括神经退行性疾病和遗传性精神发育迟滞（MR））机制的理解方面具有非常重要和影响力。因此，我们创造了第一个果蝇模型的充电综合征，一种罕见的常染色体显性形式的精神发育迟滞。使用我们的新模型，我们将确定哪些基因在功能上有助于果蝇的CHARGE综合征，希望这项研究将为CHARGE综合征患者带来新的诊断工具和/或治疗靶点。

DESCRIPTION (provided by applicant): CHARGE Syndrome (CS) is a rare, autosomal dominant disorder that is characterized by a variety of clinical symptoms. The most common of these include Coloboma, Choanal atresia, abnormal semicircular canals, heart defects, mental retardation, retardation of growth, and genital and ear anomalies, making CS a common cause of congenital anomalies. It is prevalent in approximately 1 in every 10,000 live births, and is caused in large part by loss of function mutations in the human Chd7 gene (haploinsufficiency in Chd7). Mutations in Chd7 account for some 2/3 of all patients diagnosed with CS, though little is known about the genes (and cellular processes) this protein regulates. The long term goal of this project is a deeper understanding of the mechanism(s) of pathogenesis of CS through characterization and application of a novel Drosophila model of the disease. Our hope is that research proposed here will ultimately lead to new diagnostic tools and/or therapeutic targets for treatment in patients with CS. Attempts to understand the complex etiology of many human diseases have been improved through the study of model organisms. The fruit fly, Drosophila melanogaster, has been tremendously important and influential in furthering our understanding of the mechanisms of a variety of human diseases. Using an RNA-interference (RNAi) gene knockdown strategy, we have created the first Drosophila model for CS in adult flies. Because kis, and its human homolog Chd7, encode transcription factors, the identification of biologically relevant target genes whose expression is regulated by these transcription factors, and whose function also contributes towards disease pathology will be critically required for a better understanding of this disease's pathogenesis, as well as a better rational design towards therapeutic intervention and/or diagnostic and prognostic indicators. As a model organism, Drosophila are unsurpassed as a tool of gene discovery and functional gene analysis. Using both genetic screening and microarray analysis in Drosophila, we have identified a number of target genes whose expression is regulated by kis function. Many of these target genes have the potential to contribute to one or more aspects of disease pathology. We wish to further test which of the genes that we have identified might contribute to specific aspects of disease pathology in CS through the following specific aim: to employ genetic, behavioral, and cell biological methods to further characterize which Kismet target genes may be biologically relevant to the disease symptoms observed in CS. We will specifically focus our analysis on gross motor dysfunction, intellectual disability, and defects in neuronal morphology. PUBLIC HEALTH RELEVANCE: The fruit fly, Drosophila melanogaster, has been tremendously important and influential in furthering our understanding of the mechanisms of a variety of human diseases, including neurodegenerative diseases, and forms of hereditary mental retardation (MR). Thus, we have created the first Drosophila model for CHARGE Syndrome, an uncommon autosomal dominant form of mental retardation. Using our new model, we will determine what genes functionally contribute to CHARGE Syndrome in flies, with the hope that the research proposed will lead to novel diagnostic tools and/or therapeutic targets for patients with CHARGE Syndrome.