Proteomics in Drosophila to Identify Autism Candidate Substrates of UBE3A

果蝇蛋白质组学鉴定 UBE3A 的自闭症候选底物

基本信息

项目摘要

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASD) affect ~60 in 10,000 children but in only ~10% of these individuals is autism associated with a recognized cause. Understanding the molecular pathways dysregulated in Angelman syndrome (AS), a rare and severe developmental disorder related to autism, may provide key insights leading to identification of autism susceptibility genes and pathways. Approximately 3% of all autism cases result from maternal duplications of the region containing the AS gene UBE3A. Variants in genes encoding protein targets of the ubiquitin ligase UBE3A may, therefore, confer a genetic susceptibility to autism or even cause an ASD phenotype. Here we describe a proteomics strategy utilizing the powerful genetic model organism Drosophila melanogaster to identify protein targets of human UBE3A and fly Dube3a. UBE3A will be over-expressed in the brains of flies using the GAL4/UAS system in order to increase or decrease the levels of UBE3A/Dube3a protein targets. We will then identify these targets by Rotofor-assisted proteomic profiling and mass spectrometry. Potential targets will be validated though genetic interactions in the eye and neuromuscular junction, binding assays in 293T cells and immunohistochemistry in the brains of both Ube3a-deficient and over-expressing mice. We anticipate that these studies will provide us with new autism candidate genes for future validation in families that demonstrate heritable autism risk. To this end, we propose the following specific aims: Specific Aim 1: To identify potential UBE3A and Dube3a regulated proteins using proteomic profiling in Drosophila head extracts. Completion of this aim will result in a collection of potential Dube3a and UBE3A regulated proteins for subsequent validation and autism genetic studies. Specific Aim 2: To validate physical, biochemical and genetic interactions between potential targets and Dube3a. This aim will test the hypothesis that the proteins detected in Aim #1 are regulated directly or indirectly by Dube3a. Specific Aim 3: To determine if UBE3A regulated protein expression patterns are altered in the brains of Ube3a deficient and over-expression mice. This aim will demonstrate a link between Ube3a target proteins and altered brain function in the mouse models of Angelman syndrome and proximal 15q duplication autism. PUBLIC HEALTH RELEVANCE: The primary goal of this research is to identify proteins regulated by UBE3A and to investigate the possibility that these proteins are also dysregulated or mutated in some cases of autism. Understanding how increased levels of UBE3A result in an autism phenotype at the molecular level will help us better identify and treat the underlying liability in idopathic autism.
描述(由申请人提供):自闭症谱系障碍(ASD)影响10,000名儿童中的约60名,但这些人中只有约10%是与公认原因相关的自闭症。了解Angelman综合征(AS)中失调的分子通路,这是一种与自闭症相关的罕见且严重的发育障碍,可能会为识别自闭症易感基因和通路提供关键见解。大约3%的自闭症病例是由于母亲重复了含有AS基因UBE 3A的区域。因此,编码泛素连接酶UBE 3A的蛋白质靶标的基因的变体可能赋予自闭症的遗传易感性,甚至导致ASD表型。在这里,我们描述了一个蛋白质组学策略,利用强大的遗传模式生物果蝇,以确定蛋白质目标的人UBE 3A和苍蝇Dube 3a。使用GAL 4/UAS系统将UBE 3A在果蝇的大脑中过表达,以增加或降低UBE 3A/Dube 3a蛋白靶标的水平。然后,我们将通过Rotofor辅助的蛋白质组学分析和质谱来识别这些目标。通过眼睛和神经肌肉接头中的遗传相互作用、293 T细胞中的结合测定和Ube 3a缺陷和过表达小鼠大脑中的免疫组织化学,将验证潜在靶点。我们预计,这些研究将为我们提供新的自闭症候选基因,以供将来在表现出遗传性自闭症风险的家庭中进行验证。为此,我们提出了以下具体目标:具体目标1:确定潜在的UBE 3A和Dube 3a调节蛋白质使用蛋白质组学分析在果蝇头部提取物。这一目标的完成将导致潜在的Dube 3a和UBE 3A调节蛋白的收集,用于随后的验证和自闭症遗传学研究。具体目标2:验证潜在靶标与Dube 3a之间的物理、生化和遗传相互作用。该目的将检验在目的#1中检测到的蛋白质直接或间接受Dube 3a调节的假设。具体目标3:确定Ube 3a缺陷和过表达小鼠脑中UBE 3A调节蛋白表达模式是否改变。这一目标将证明Ube 3a靶蛋白与Angelman综合征和近端15 q重复自闭症小鼠模型中脑功能改变之间的联系。公共卫生相关性:这项研究的主要目标是鉴定由UBE 3A调控的蛋白质,并研究这些蛋白质在某些自闭症病例中也失调或突变的可能性。了解UBE 3A水平的增加如何在分子水平上导致自闭症表型,将有助于我们更好地识别和治疗特发性自闭症的潜在责任。

项目成果

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LAWRENCE T REITER其他文献

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{{ truncateString('LAWRENCE T REITER', 18)}}的其他基金

The role of UBE3A in gliopathic seizures
UBE3A 在胶质病性癫痫发作中的作用
  • 批准号:
    10451603
  • 财政年份:
    2020
  • 资助金额:
    $ 1万
  • 项目类别:
The role of UBE3A in gliopathic seizures
UBE3A 在胶质病性癫痫发作中的作用
  • 批准号:
    10266138
  • 财政年份:
    2020
  • 资助金额:
    $ 1万
  • 项目类别:
The role of UBE3A in gliopathic seizures
UBE3A 在胶质病性癫痫发作中的作用
  • 批准号:
    10674705
  • 财政年份:
    2020
  • 资助金额:
    $ 1万
  • 项目类别:
The role of UBE3A in gliopathic seizures
UBE3A 在胶质病性癫痫发作中的作用
  • 批准号:
    10116136
  • 财政年份:
    2020
  • 资助金额:
    $ 1万
  • 项目类别:
Tooth pulp as a source for neuronal precursor cells to study neurogenetic disorde
牙髓作为神经元前体细胞的来源来研究神经遗传疾病
  • 批准号:
    8299874
  • 财政年份:
    2012
  • 资助金额:
    $ 1万
  • 项目类别:
Tooth pulp as a source for neuronal precursor cells to study neurogenetic disorde
牙髓作为神经元前体细胞的来源来研究神经遗传疾病
  • 批准号:
    8413042
  • 财政年份:
    2012
  • 资助金额:
    $ 1万
  • 项目类别:
Proteomics in Drosophila to Identify Autism Candidate Substrates of UBE3A
果蝇蛋白质组学鉴定 UBE3A 的自闭症候选底物
  • 批准号:
    7914309
  • 财政年份:
    2008
  • 资助金额:
    $ 1万
  • 项目类别:
Proteomics in Drosophila to Identify Autism Candidate Substrates of UBE3A
果蝇蛋白质组学鉴定 UBE3A 的自闭症候选底物
  • 批准号:
    8144307
  • 财政年份:
    2008
  • 资助金额:
    $ 1万
  • 项目类别:
Proteomics in Drosophila to Identify Autism Candidate Substrates of UBE3A
果蝇蛋白质组学鉴定 UBE3A 的自闭症候选底物
  • 批准号:
    8292310
  • 财政年份:
    2008
  • 资助金额:
    $ 1万
  • 项目类别:
Proteomics in Drosophila to Identify Autism Candidate Substrates of UBE3A
果蝇蛋白质组学鉴定 UBE3A 的自闭症候选底物
  • 批准号:
    7576681
  • 财政年份:
    2008
  • 资助金额:
    $ 1万
  • 项目类别:

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