Modeling Fragile X Syndrome in Drosophila

果蝇脆性 X 综合征建模

• 批准号: 6949152
• 负责人: THOMAS A JONGENS
• 金额: $ 32.99万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6949152
• 关键词: Drosophilidae; RNA binding protein; arthropod genetics; behavioral /social science research tag; behavioral genetics; developmental genetics; developmental neurobiology; disease /disorder model; fragile X syndromes; gene mutation; genetic regulation; memory; neurotransmitter antagonist; sex behavior

DESCRIPTION (provided by applicant): Fragile X syndrome is one of the most commonly inherited forms of human mental retardation with an incidence rate of 1 in 4000 males and 1 in 6000 females. It is caused by the loss of FMR1 gene function. Patients with Fragile X syndrome suffer from a variety of symptoms including; mental retardation, attention deficit, hyperactivity, sleep disorders, anxiety, unstable mood and autistic-like behaviors. Physical defects include macroorchidism and irregular dendritic spine morphology. In previous studies, our lab developed a Fragile X model in Drosophila. This model is based on the dfmr1 (also called dfxr) gene, which has a high degree of sequence identity/similarity to the FMR1 gene. The dFMR1 protein has similar RNA binding properties, developmental expression pattern and subcellular distribution to the FMR1 protein (FMRP). In recent studies, we have shown that dfmr1 null mutants display several behavioral defects that bear similarity to symptoms of Fragile X patients. The relevant phenotypes in Drosophila include arrhythmic circadian behavior, attention deficit during courtship, memory defects and subtle defects of neuronal morphology. The similarities in the biochemical properties of dFMR1 and FMRP and their loss of function phenotypes suggest that these two proteins have conserved function in similar behavioral and developmental processes. Thus the Drosophila dfmr1 mutants are a relevant model to study aspects of Fragile X syndrome. To ameliorate Fragile X syndrome it is imperative that we understand when and how FMR1 activity functions to prevent cognitive and behavioral defects. The temporal requirements and molecular role of FMR1 are currently not known. We propose to use the Drosophila model of Fragile X to determine when dfmr1 activity is required to determine if the behavioral defects are due to developmental or physiological defects. We are also investigating possible physiological pathways affected by loss of dfmr1 function. Through these studies we have identified a pharmacological treatment that rescues the courtship and memory defects displayed in our dfmr1 mutants. In this proposal we will determine and verify a route of action of this drug to identify potential targets for the treatment of Fragile X syndrome.

描述（由申请人提供）： 脆性 X 综合征是人类智力低下最常见的遗传形式之一，其发病率为 4000 名男性和 6000 名女性中有 1 人。它是由 FMR1 基因功能丧失引起的。脆性 X 综合征患者会出现多种症状，包括：智力低下、注意力缺陷、多动、睡眠障碍、焦虑、情绪不稳定和自闭症样行为。物理缺陷包括大睾丸和不规则的树突棘形态。在之前的研究中，我们的实验室开发了果蝇脆性X模型。该模型基于 dfmr1（也称为 dfxr）基因，该基因与 FMR1 基因具有高度的序列同一性/相似性。 dFMR1 蛋白与 FMR1 蛋白 (FMRP) 具有相似的 RNA 结合特性、发育表达模式和亚细胞分布。在最近的研究中，我们发现 dfmr1 无效突变体表现出几种与脆性 X 细胞患者症状相似的行为缺陷。果蝇的相关表型包括节律失常的昼夜节律行为、求爱期间的注意力缺陷、记忆缺陷和神经元形态的微妙缺陷。 dFMR1 和 FMRP 生化特性的相似性及其功能丧失表型表明这两种蛋白在相似的行为和发育过程中具有保守的功能。因此，果蝇 dfmr1 突变体是研究脆性 X 综合征的相关模型。为了改善脆性 X 综合征，我们必须了解 FMR1 活性何时以及如何发挥作用，以预防认知和行为缺陷。 FMR1 的时间要求和分子作用目前尚不清楚。我们建议使用 Fragile X 的果蝇模型来确定何时需要 dfmr1 活性来确定行为缺陷是否是由于发育或生理缺陷所致。我们还在研究 dfmr1 功能丧失影响的可能生理途径。通过这些研究，我们确定了一种药物治疗方法，可以挽救 dfmr1 突变体中表现出的求爱和记忆缺陷。在本提案中，我们将确定并验证该药物的作用途径，以确定治疗脆性 X 综合征的潜在靶点。