Characterization of a novel Drosophila disease model for CHARGE Syndrome

电荷综合征的新型果蝇疾病模型的表征

• 批准号: 8076225
• 负责人: Daniel R Marenda
• 金额: $ 22.87万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076225
• 关键词: Accounting; Adult; Affect; Anabolism; Animal Model; Behavioral Genetics; Biocompatible Materials; Biological; CHARGE syndrome; Cell membrane; Cell physiology; Cells; Characteristics; Choanal Atresia; Chromatin Structure; Clinical; Coloboma; Complex; Congenital Heart Defects; DNA Binding; Defect; Development; Diagnosis; Diagnostic; Disease; Disease model; Drosophila genus; Drosophila melanogaster; Ear; Etiology; Exhibits; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic Screening; Genetic Transcription; Genital system; Glutamates; Goals; Grant; Growth; Homologous Gene; Human; Influentials; Inherited; Intellectual functioning disability; Intervention; Lead; Ligands; Live Birth; Mammalian Cell; Mental Retardation; Methods; Microarray Analysis; Modeling; Molecular; Morphology; Motor; Mutation; NIH Program Announcements; Neurodegenerative Disorders; Neurons; Online Mendelian Inheritance In Man; Pathogenesis; Pathology; Patients; Pharmacotherapy; Phenotype; Production; Protein Family; Proteins; Psyche structure; RNA Interference; Regulation; Research; Semicircular canal structure; Signal Transduction; Study models; Symptoms; Synaptic Transmission; Testing; Therapeutic Intervention; Time; Validation; animal model development; design; efficacy testing; fly; gene discovery; gene function; helicase; human disease; improved; loss of function mutation; meetings; member; nervous system development; novel; novel diagnostics; prognostic indicator; promoter; public health relevance; receptor; response; therapeutic target; tool; transcription factor

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.

描述（由申请人提供）：电荷综合征（CS）是一种罕见的常染色体显性疾病，其特征是多种临床症状。其中最常见的是coloboma，choanal闭锁，异常半圆管，心脏缺陷，智力低下，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。它在每10,000个活生生中大约有1个普遍存在，并且很大程度上是由于人类CHD7基因的功能突变（CHD7中的单倍弥补）而引起的。 CHD7中的突变占所有被诊断为CS的患者的2/3，尽管对这种蛋白质调节的基因（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该疾病的新型果蝇模型来深入了解CS发病机理的机制。我们的希望是，这里提出的研究最终将导致CS患者治疗的新诊断工具和/或治疗靶标。 通过研究模型生物的研究，已经改善了了解许多人类疾病的复杂病因的尝试。果蝇果蝇果蝇（Drosophila Melanogaster）非常重要，并且在进一步了解我们对各种人类疾病机制的理解方面非常重要。使用RNA脱粒（RNAI）基因敲低策略，我们创建了第一个用于成年蝇中CS的果蝇模型。因为KIS及其人类同源物CHD7编码转录因子，因此对生物学相关的靶基因的鉴定，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有助于更好地理解该疾病的发病机理，以及更好地理解该疾病的发病机理，以及对治疗性干预和/或诊断和/或诊断和诊断和诊断和预测的更好的处理设计。作为模型生物体，果蝇无与伦比作为基因发现和功能基因分析的工具。使用果蝇中的遗传筛查和微阵列分析，我们已经确定了许多靶基因，其表达受KIS功能调节。这些靶基因中的许多都有可能为疾病病理的一个或多个方面做出贡献。我们希望通过以下特定目的进一步测试我们确定的哪些基因可能有助于CS中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中观察到的疾病症状在生物学上相关。我们将专门将分析集中在神经元形态的总体运动功能障碍，智力障碍和缺陷上。 公共卫生相关性：果蝇，果蝇Melanogaster，在进一步了解我们对各种人类疾病机制的理解方面非常重要，并且具有影响力，包括神经退行性疾病，以及遗传性心理障碍的形式（MR）。因此，我们创建了第一个用于电荷综合征的果蝇模型，这是一种罕见的常染色体主导性智力低位形式。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中的电荷综合征，并希望该研究提出的研究将导致用于电荷综合征患者的新型诊断工具和/或治疗靶标。