A multi-species approach to find regulators of deafness genes

寻找耳聋基因调节因子的多物种方法

基本信息

  • 批准号:
    9207570
  • 负责人:
  • 金额:
    $ 42.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-12-01 至 2021-11-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Genetic screens in mice and the naturally occurring genetic variation in humans have provided a valuable resource to identify genes implicated in hair cell function and deafness. Two examples is the identification of genes involved in Usher syndrome, the most common form of deaf-blindness, and the role of Myh9 in both syndromic and non-syndromic deafness. We have used the power of Drosophila genetics to identify new genes involved in hearing and deafness. The auditory organs of Drosophila and vertebrates have a number of molecular and functional similarities despite being widely separated in evolutionary time. We identified mutations in Ubr3, an E3 ubiquitin ligase, that cause a physical detachment of the sensory components of Johnston's organ from the fly antenna. Strikingly, this phenotype is identical to that seen in mutations in Drosophila Myosin VIIa. Since Myosin VIIa mutations in humans cause Usher Syndrome type IB, it is possible that Ubr3 may regulate Myosin VIIa function in invertebrates and vertebrates. Our data suggest that Ubr3 genetically interacts with Myosin VIIa and Ubr3 and Myosin VIIa physically and genetically interact with Drosophila homologues of two other Usher syndrome proteins, PCDH15 and Sans. However, we have found that Ubr3 does not modify Myosin VIIa, but instead mono-ubiquitinates non-muscle Myosin II. This modification increase an interaction between the two myosins, and fine-tuning the level of this interaction appears critical for Myosin VIIa function. In the present proposal, we will expand on the use of Drosophila as a model system to understand deafness by characterizing the roles of Ubr3, Myosin II and Myosin VIIa in hearing in Drosophila (Aim 1). We will then test the function of Ubr3 in the development and function of mouse hair cells, and will test whether the interaction of Myosin II and Myosin VIIa is conserved in mice (Aim 2). Finally, we will carry out a genetic screen of 3000 Drosophila genes that may be involved in human disease using newly developed protein knockdown technology to identify genes that play a role in hearing in Drosophila (Aim 3).
项目摘要 小鼠的遗传筛选和人类自然发生的遗传变异提供了一个有价值的 资源,以确定与毛细胞功能和耳聋有关的基因。两个例子是识别 与Usher综合征(最常见的致盲形式)有关的基因,以及Myh9在这两种疾病中的作用。 综合征性耳聋和非综合征性耳聋。我们利用果蝇遗传学的力量来识别新的 与听力和耳聋有关的基因。果蝇和脊椎动物的听觉器官有许多 分子和功能的相似性,尽管在进化时间上被广泛分离。我们确定 Ubr3突变,一种E3泛素连接酶,导致感觉成分的物理分离, 约翰斯顿的器官从苍蝇天线。令人惊讶的是,这种表型与在突变中看到的表型相同, 果蝇肌球蛋白VIIa.由于人类肌球蛋白VIIa突变导致IB型Usher综合征, Ubr 3可能在无脊椎动物和脊椎动物中调节肌球蛋白VIIa的功能。我们的数据表明Ubr 3 与肌球蛋白VIIa和Ubr 3发生遗传相互作用,而肌球蛋白VIIa与 果蝇的同源物的其他两个亚瑟综合征蛋白,PCDH15和Sans。然而,我们发现 Ubr3不修饰肌球蛋白VIIa,而是单泛素化非肌肉肌球蛋白II。此修改 增加两种肌球蛋白之间的相互作用,微调这种相互作用的水平似乎是至关重要的 肌球蛋白VIIa功能。 在目前的建议中,我们将扩大果蝇作为模型系统的使用,以了解耳聋, 描述了Ubr 3、肌球蛋白II和肌球蛋白VIIa在果蝇听觉中的作用(Aim 1)。然后我们将测试 Ubr3在小鼠毛细胞发育和功能中的作用,并将测试Ubr3与 肌球蛋白II和肌球蛋白VIIa在小鼠中是保守的(目的2)。最后,我们将对3000名 使用新开发的蛋白质敲除可能与人类疾病有关的果蝇基因 技术来鉴定果蝇中在听觉中起作用的基因(目标3)。

项目成果

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HUGO J BELLEN其他文献

HUGO J BELLEN的其他文献

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{{ truncateString('HUGO J BELLEN', 18)}}的其他基金

Center for functional analysis of human UDN gene homologs in Drosophila and zebrafish
果蝇和斑马鱼人类UDN基因同源物功能分析中心
  • 批准号:
    10600181
  • 财政年份:
    2022
  • 资助金额:
    $ 42.38万
  • 项目类别:
Genomic medicine and gene function implementation for an underserved population
针对服务不足人群的基因组医学和基因功能实施
  • 批准号:
    10450159
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
Functional Genomic Dissection of Alzheimer's Disease in Humans and Drosophila Models
人类和果蝇模型中阿尔茨海默病的功能基因组解剖
  • 批准号:
    10681445
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
IMPACTS OF GLIAL LIPID DROPLETS ON OXIDATIVE STRESS AND NEURODEGENERATION IN ALZHEIMER'S DISEASE
胶质脂滴对阿尔茨海默病氧化应激和神经变性的影响
  • 批准号:
    10804252
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
Genomic medicine and gene function implementation for an underserved population
针对服务不足人群的基因组医学和基因功能实施
  • 批准号:
    10640103
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
IMPACTS OF GLIAL LIPID DROPLETS ON OXIDATIVE STRESS AND NEURODEGENERATION IN ALZHEIMER'S DISEASE
胶质脂滴对阿尔茨海默病氧化应激和神经变性的影响
  • 批准号:
    10276761
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
A Comprehensive Resource for Manipulating the Drosophila Genome
操纵果蝇基因组的综合资源
  • 批准号:
    10267895
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
A Comprehensive Resource for Manipulating the Drosophila Genome
操纵果蝇基因组的综合资源
  • 批准号:
    10437006
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
IMPACTS OF GLIAL LIPID DROPLETS ON OXIDATIVE STRESS AND NEURODEGENERATION IN ALZHEIMER'S DISEASE
胶质脂滴对阿尔茨海默病氧化应激和神经变性的影响
  • 批准号:
    10640936
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
IMPACTS OF GLIAL LIPID DROPLETS ON OXIDATIVE STRESS AND NEURODEGENERATION IN ALZHEIMER'S DISEASE
胶质脂滴对阿尔茨海默病氧化应激和神经变性的影响
  • 批准号:
    10473724
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:

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