REGULATION OF THE NEUROMUSCULAR JUNCTION BY THE CYTOSKELETON-ASSOCIATED PROTEIN, ADDUCIN

细胞骨架相关蛋白内收蛋白对神经肌肉接头的调节

基本信息

  • 批准号:
    RGPIN-2018-05964
  • 负责人:
  • 金额:
    $ 2.33万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2020
  • 资助国家:
    加拿大
  • 起止时间:
    2020-01-01 至 2021-12-31
  • 项目状态:
    已结题

项目摘要

The neuromuscular junction (NMJ) includes the motoneuron terminal, the synaptic gap and post-synaptic muscle. My research program seeks to understand how the post-synaptic region of the NMJ is constructed and is modified by synaptic activity, using the fruit fly (Drosophila) as a model. The long-term goal of my research program is focused on understanding how the cytoskeleton of the post synapse regulates the morphology and function of the NMJ as it is a protein lattice upon which critical synaptic proteins such as scaffolding molecules and neurotransmitter receptors are integrated. We have found that the cytoskeletal protein adducin (Add; known as Hts in Drosophila: Add/Hts), an actin-spectrin binding protein, regulates synapse structure at the NMJ. In Drosophila, we found that post-synaptic Add/Hts over-expression causes NMJ synaptic overgrowth and the phosphorylation of the NMJ scaffolding molecule Discs large (Dlg), a membrane-associated guanylate kinase with homology to SAP-97. We have data that Add/Hts also translocates to the nucleus, likely from the synapse, suggesting that Add/Hts is a synapto-nuclear protein. Our short-term objectives include: Aim 1: To examine Add/Hts distribution at the NMJ synapse in relation to other proteins including Dlg: We hypothesize that when Add/Hts is phosphorylated following synaptic activation it translocates away from the synapse to the cell nucleus where it alters nuclear export of transcripts for several kinases (e.g. Ca2+/calmodulin-dependent protein kinase II; CaMKII) which phosphorylate Dlg leading to a delocalization of Dlg at the synapse. These actions will de-stabilize' the synapse allowing growth or retraction to occur. Aim 2: To determine the role of Add/Hts in the cell nucleus: We will identify molecular interactions between Add/Hts and other nuclear proteins and RNA species, such as CaMKII transcripts. Aim 3: To explore the role of Add/Hts as a regulator of export from the nucleus: We will determine the mechanism by which Add/Hts alters the levels of specific protein kinases in the synapse including CaMKII and partitioning defective-1/ microtubule affinity-regulating kinase, both of which phosphorylate Dlg, and whether Add/Hts actions in the cell nucleus assists in the export of transcripts for these protein kinases. This work is original and important as our previous and preliminary data point to a novel view of how cytoskeletal-associated proteins modify synaptic function. We now think that signaling information in the synapse does not stay in the synapse, but is disseminated widely in the cell, including to the nucleus, likely by Add/Hts itself, as well as other molecules. The proposed experiments provide a relatively simple, tractable model of how the functions of Add/Hts can be determined in an intact animal and lead to an understanding of how it can regulate synaptic form and function at the NMJ.
神经肌肉接头(NMJ)包括运动神经元末梢、突触间隙和突触后肌。我的研究计划旨在了解NMJ的突触后区域是如何构建的,并通过突触活动进行修改,使用果蝇(果蝇)作为模型。我的研究计划的长期目标是专注于了解突触后的细胞骨架如何调节NMJ的形态和功能,因为它是一个蛋白质晶格,关键的突触蛋白如支架分子和神经递质受体被整合。我们已经发现,细胞骨架蛋白内收蛋白(Add;在果蝇中称为Hts:Add/Hts),一种肌动蛋白血影蛋白结合蛋白,调节NMJ的突触结构。在果蝇中,我们发现突触后Add/Hts过度表达导致NMJ突触过度生长和NMJ支架分子Discs large(Dlg)(一种与SAP-97同源的膜相关鸟苷酸激酶)的磷酸化。我们有数据表明Add/Hts也可能从突触易位到细胞核,这表明Add/Hts是一种突触核蛋白。 我们的短期目标包括: 目标1:为了检查NMJ突触处的Add/Hts分布与包括Dlg在内的其他蛋白质的关系:我们假设,当Add/Hts在突触激活后被磷酸化时,它从突触易位到细胞核,在那里它改变了几种激酶(例如Ca 2 +/钙调蛋白依赖性蛋白激酶II; CaMKII)的转录物的核输出,这些激酶磷酸化Dlg,导致Dlg在突触处的离域。这些动作会使突触失去稳定,从而允许生长或收缩发生。 目标二:为了确定Add/Hts在细胞核中的作用:我们将确定Add/Hts与其他核蛋白和RNA种类(如CaMKII转录本)之间的分子相互作用。 目标3:探讨添加/Hts作为从细胞核出口的调节剂的作用:我们将确定添加/Hts改变突触中特定蛋白激酶水平的机制,包括CaMKII和分区缺陷-1/微管亲和力调节激酶,这两者都磷酸化Dlg,以及添加/Hts在细胞核中的作用是否有助于这些蛋白激酶的转录本的出口。 这项工作是原始的和重要的,因为我们以前的和初步的数据点,以一种新的观点,细胞相关的蛋白质如何修改突触功能。我们现在认为,突触中的信号信息并不停留在突触中,而是在细胞中广泛传播,包括细胞核,可能是通过Add/Hts本身以及其他分子。拟议的实验提供了一个相对简单,易于处理的模型,如何添加/Hts的功能可以在一个完整的动物,并导致了解它如何可以调节突触的形式和功能在NMJ。

项目成果

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Krieger, Charles其他文献

Submyeloablative conditioning with busulfan permits bone marrow-derived cell accumulation in a murine model of Alzheimer's disease
  • DOI:
    10.1016/j.neulet.2015.01.023
  • 发表时间:
    2015-02-19
  • 期刊:
  • 影响因子:
    2.5
  • 作者:
    Barr, Christine M.;Manning, John;Krieger, Charles
  • 通讯作者:
    Krieger, Charles
Making the connection - shared molecular machinery and evolutionary links underlie the formation and plasticity of occluding junctions and synapses
  • DOI:
    10.1242/jcs.186627
  • 发表时间:
    2016-08-15
  • 期刊:
  • 影响因子:
    4
  • 作者:
    Harden, Nicholas;Wang, Simon Ji Hau;Krieger, Charles
  • 通讯作者:
    Krieger, Charles
Fus gene mutations in familial and sporadic amyotrophic lateral sclerosis.
  • DOI:
    10.1002/mus.21665
  • 发表时间:
    2010-08
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
    Rademakers, Rosa;Stewart, Heather;Dejesus-Hernandez, Mariely;Krieger, Charles;Graff-Radford, Neill;Fabros, Marife;Briemberg, Hannah;Cashman, Neil;Eisen, Andrew;Mackenzie, Ian R. A.
  • 通讯作者:
    Mackenzie, Ian R. A.
Bone Marrow-Derived Cells in the Central Nervous System of a Mouse Model of Amyotrophic Lateral Sclerosis are Associated with Blood Vessels and Express CX3CR1
  • DOI:
    10.1002/glia.20859
  • 发表时间:
    2009-10-01
  • 期刊:
  • 影响因子:
    6.2
  • 作者:
    Lewis, Coral-Ann B.;Solomon, Jennifer N.;Krieger, Charles
  • 通讯作者:
    Krieger, Charles

Krieger, Charles的其他文献

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{{ truncateString('Krieger, Charles', 18)}}的其他基金

REGULATION OF THE NEUROMUSCULAR JUNCTION BY THE CYTOSKELETON-ASSOCIATED PROTEIN, ADDUCIN
细胞骨架相关蛋白内收蛋白对神经肌肉接头的调节
  • 批准号:
    RGPIN-2018-05964
  • 财政年份:
    2022
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
REGULATION OF THE NEUROMUSCULAR JUNCTION BY THE CYTOSKELETON-ASSOCIATED PROTEIN, ADDUCIN
细胞骨架相关蛋白内收蛋白对神经肌肉接头的调节
  • 批准号:
    RGPIN-2018-05964
  • 财政年份:
    2021
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
REGULATION OF THE NEUROMUSCULAR JUNCTION BY THE CYTOSKELETON-ASSOCIATED PROTEIN, ADDUCIN
细胞骨架相关蛋白内收蛋白对神经肌肉接头的调节
  • 批准号:
    RGPIN-2018-05964
  • 财政年份:
    2019
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
REGULATION OF THE NEUROMUSCULAR JUNCTION BY THE CYTOSKELETON-ASSOCIATED PROTEIN, ADDUCIN
细胞骨架相关蛋白内收蛋白对神经肌肉接头的调节
  • 批准号:
    RGPIN-2018-05964
  • 财政年份:
    2018
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
ADDUCIN REGULATES THE NEUROMUSCULAR JUNCTION IN DROSOPHILA
内收蛋白调节果蝇的神经肌肉接头
  • 批准号:
    171372-2012
  • 财政年份:
    2016
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
ADDUCIN REGULATES THE NEUROMUSCULAR JUNCTION IN DROSOPHILA
内收蛋白调节果蝇的神经肌肉接头
  • 批准号:
    171372-2012
  • 财政年份:
    2015
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
ADDUCIN REGULATES THE NEUROMUSCULAR JUNCTION IN DROSOPHILA
内收蛋白调节果蝇的神经肌肉接头
  • 批准号:
    171372-2012
  • 财政年份:
    2014
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
ADDUCIN REGULATES THE NEUROMUSCULAR JUNCTION IN DROSOPHILA
内收蛋白调节果蝇的神经肌肉接头
  • 批准号:
    171372-2012
  • 财政年份:
    2013
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
ADDUCIN REGULATES THE NEUROMUSCULAR JUNCTION IN DROSOPHILA
内收蛋白调节果蝇的神经肌肉接头
  • 批准号:
    171372-2012
  • 财政年份:
    2012
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
Adducin phosphorylation regulates cell morphology and function in neurons, glia and muscle
内收蛋白磷酸化调节神经元、神经胶质和肌肉的细胞形态和功能
  • 批准号:
    171372-2006
  • 财政年份:
    2010
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual

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REGULATION OF THE NEUROMUSCULAR JUNCTION BY THE CYTOSKELETON-ASSOCIATED PROTEIN, ADDUCIN
细胞骨架相关蛋白内收蛋白对神经肌肉接头的调节
  • 批准号:
    RGPIN-2018-05964
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  • 批准号:
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REGULATION OF THE NEUROMUSCULAR JUNCTION BY THE CYTOSKELETON-ASSOCIATED PROTEIN, ADDUCIN
细胞骨架相关蛋白内收蛋白对神经肌肉接头的调节
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