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病，以多种临床症状为特征。其中最常见的包括结肠畸形、后肛门闭锁、半规管异常、心脏缺陷、智力迟钝、生长迟缓、生殖器和耳朵异常，使CS成为先天性异常的常见原因。大约每10000个活产婴儿中就有1人患此病，主要是由于人类Chd7基因的功能突变缺失（Chd7单倍缺陷）。Chd7突变约占所有CS患者的2/3，尽管人们对这种蛋白质调控的基因（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。我们希望这里提出的研究将最终导致新的诊断工具和/或治疗CS患者的治疗靶点。通过对模式生物的研究，了解许多人类疾病的复杂病因学的尝试得到了改进。果蝇（Drosophila melanogaster）在促进我们对各种人类疾病机制的理解方面发挥了极其重要和有影响力的作用。利用rna干扰（RNAi）基因敲低策略，我们在成年果蝇中创建了第一个果蝇CS模型。由于kis及其人类同源基因Chd7编码转录因子，因此鉴定生物学上相关的靶基因（其表达受这些转录因子调节，其功能也有助于疾病病理）对于更好地了解该疾病的发病机制以及更好地合理设计治疗干预和/或诊断和预后指标至关重要。作为一种模式生物，果蝇作为基因发现和功能基因分析的工具是无与伦比的。通过对果蝇的基因筛选和微阵列分析，我们已经确定了一些表达受kis功能调控的靶基因。这些靶基因中的许多都有可能导致疾病病理的一个或多个方面。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疾病病理的特定方面：采用遗传，行为和细胞生物学方法进一步表征哪些Kismet靶基因可能与CS观察到的疾病症状具有生物学相关性。我们将特别集中分析大运动功能障碍、智力残疾和神经元形态缺陷。

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.