Revealing protein synthesis defects in Fragile X Syndrome with new chemical tools

利用新的化学工具揭示脆性 X 综合征的蛋白质合成缺陷

基本信息

  • 批准号:
    8328886
  • 负责人:
  • 金额:
    $ 34.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-09-15 至 2015-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Fragile X syndrome is the most common genetic cause of autism, occurring in 1 out of 6000 births. Affected patients also suffer from mental retardation and in some cases seizures. Current treatments involve the use of drugs to ameliorate mood and attention symptoms and to prevent seizures, but are not able to restore normal learning and emotional function. A molecular-level understanding of the neuronal defects in Fragile X syndrome will be necessary for the rational design of therapies to address the underlying cause of the disease. The protein mutated in the disease, the Fragile X mental retardation protein (FMRP), is required for regulating protein synthesis at activated synapses, the communication points between neurons. A large body of evidence suggests that the normal strengthening and weakening of synapses that underlies learning requires the careful regulation of protein synthesis by synaptic activity. Experiments have also suggested a role for FMRP in regulating both synaptic strengthening and weakening. However, the precise relationship between synaptic strengthening and weakening, protein synthesis, and FMRP is poorly understood. For instance, which proteins are synthesized during, utilized in, or required for synaptic strengthening and weakening, and which of these events are affected by FMRP loss, is not known. Research on the function of FMRP in activity-dependent local protein synthesis has been limited by the low sensitivity and resolution of methods for assessing and controlling protein synthesis in living neurons. We have developed new molecular tools that allow the real-time tracking and control of new protein synthesis and the visualization of kinase pathways involved in activity-induced protein synthesis. We propose to use these tools to examine the specificity of protein synthesis responses in synaptic strengthening versus weakening, and to study the effect of FMRP loss on these responses. We will also determine which new proteins are normally required for long-lasting synaptic plasticity, and how FMRP loss might alter those requirements. These studies will provide insight into the regulation and function of synaptic protein synthesis in persistent synaptic plasticity, identify potential molecular targets for therapeutic intervention, and produce new technologies that can benefit the larger neuroscience community.
描述(由申请人提供):脆性X染色体综合征是自闭症最常见的遗传原因,每6000个新生儿中就有1个。受影响的患者还会出现智力迟钝,在某些情况下还会出现癫痫发作。目前的治疗方法包括使用药物来改善情绪和注意力症状,防止癫痫发作,但不能恢复正常的学习和情绪功能。在分子水平上理解脆性X综合征中的神经元缺陷对于合理设计治疗方法以解决该疾病的根本原因是必要的。在这种疾病中发生突变的蛋白质是脆性X智力迟钝蛋白(FMRP),它是调节激活突触(神经元之间的通讯点)的蛋白质合成所必需的。大量证据表明,作为学习基础的突触的正常增强和减弱需要通过突触活动仔细调节蛋白质合成。实验还表明FMRP在调节突触增强和减弱方面发挥作用。然而,突触增强和减弱、蛋白质合成和FMRP之间的确切关系尚不清楚。例如,哪些蛋白质是在突触增强和减弱过程中合成、利用或需要的,以及这些事件中的哪些受到FMRP丢失的影响,这些都是未知的。FMRP在活性依赖的局部蛋白质合成中的功能研究一直受到活体神经元蛋白质合成评估和控制方法的低灵敏度和分辨率的限制。我们已经开发了新的分子工具,可以实时跟踪和控制新的蛋白质合成,并可视化参与活性诱导的蛋白质合成的激酶途径。我们建议使用这些工具来检查突触增强与减弱中蛋白质合成反应的特异性,并研究FMRP丢失对这些反应的影响。我们还将确定哪些新的蛋白质通常需要持久的突触可塑性,以及FMRP的丢失如何改变这些需求。这些研究将深入了解突触蛋白合成在持续突触可塑性中的调节和功能,确定治疗干预的潜在分子靶点,并产生新的技术,可以使更大的神经科学界受益。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Michael Z. Lin其他文献

Synaptic basis of feature selectivity in hippocampal neurons
海马神经元特征选择性的突触基础
  • DOI:
    10.1038/s41586-024-08325-9
  • 发表时间:
    2024-12-18
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Kevin C. Gonzalez;Adrian Negrean;Zhenrui Liao;Satoshi Terada;Guofeng Zhang;Sungmoo Lee;Katalin Ócsai;Balázs J. Rózsa;Michael Z. Lin;Franck Polleux;Attila Losonczy
  • 通讯作者:
    Attila Losonczy
An optimized luciferin formulation for NanoLuc-based in vivo bioluminescence imaging
用于基于 NanoLuc 的体内生物发光成像的优化荧光素制剂
  • DOI:
    10.1038/s41598-025-97366-9
  • 发表时间:
    2025-04-15
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Chao Gao;Yan Wu;Connor Fitzgerald;Hui Wang;Tim Ugo;Tetsuo Uyeda;Wenhui Zhou;Yichi Su;Thomas A. Kirkland;Michael Z. Lin
  • 通讯作者:
    Michael Z. Lin
Pharmacodynamics of Akt drugs revealed by a kinase-modulated bioluminescent indicator
一种激酶调节的生物发光指示剂揭示的 Akt 药物的药效学
  • DOI:
    10.1038/s41589-025-01846-y
  • 发表时间:
    2025-02-11
  • 期刊:
  • 影响因子:
    13.700
  • 作者:
    Yan Wu;Chenzhou Hao;Chao Gao;Matt Hageman;Sungmoo Lee;Thomas A. Kirkland;Nathanael S. Gray;Yichi Su;Michael Z. Lin
  • 通讯作者:
    Michael Z. Lin
On the cutting edge: protease-based methods for sensing and controlling cell biology
处于前沿:基于蛋白酶的细胞生物学传感与控制方法
  • DOI:
    10.1038/s41592-020-0891-z
  • 发表时间:
    2020-07-13
  • 期刊:
  • 影响因子:
    32.100
  • 作者:
    H. Kay Chung;Michael Z. Lin
  • 通讯作者:
    Michael Z. Lin
Functional and Structural Characterization of A New Monomeric Far-Red Fluorescent Protein
  • DOI:
    10.1016/j.bpj.2009.12.1158
  • 发表时间:
    2010-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Michael Z. Lin;Michael R. McKeown;Ho Leung Ng;Tom Alber;Roger Y. Tsien
  • 通讯作者:
    Roger Y. Tsien

Michael Z. Lin的其他文献

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{{ truncateString('Michael Z. Lin', 18)}}的其他基金

Development of selective and potent protease inhibitors for corona and other pandemic viruses
开发针对冠状病毒和其他大流行病毒的选择性有效蛋白酶抑制剂
  • 批准号:
    10514273
  • 财政年份:
    2022
  • 资助金额:
    $ 34.05万
  • 项目类别:
The power of positivity: a novel class of voltage indicators for high-fidelity brain activity imaging
积极性的力量:用于高保真大脑活动成像的新型电压指示器
  • 批准号:
    10294164
  • 财政年份:
    2021
  • 资助金额:
    $ 34.05万
  • 项目类别:
Chemogenetic control of kinase and phosphatase activity by modulating autoinhibition
通过调节自抑制对激酶和磷酸酶活性进行化学遗传学控制
  • 批准号:
    10195182
  • 财政年份:
    2021
  • 资助金额:
    $ 34.05万
  • 项目类别:
Bioluminescent indicators for noninvasive imaging of acetylcholine release
用于乙酰胆碱释放无创成像的生物发光指示器
  • 批准号:
    10196839
  • 财政年份:
    2021
  • 资助金额:
    $ 34.05万
  • 项目类别:
Chemogenetic control of kinase and phosphatase activity by modulating autoinhibition
通过调节自抑制对激酶和磷酸酶活性进行化学遗传学控制
  • 批准号:
    10371123
  • 财政年份:
    2021
  • 资助金额:
    $ 34.05万
  • 项目类别:
Noninvasive bioluminescent imaging of neuronal activity in freely behaving animals
自由行为动物神经元活动的无创生物发光成像
  • 批准号:
    9906190
  • 财政年份:
    2019
  • 资助金额:
    $ 34.05万
  • 项目类别:
Protein voltage sensors: kilohertz imaging of neural dynamics in behaving animals
蛋白质电压传感器:行为动物神经动力学的千赫兹成像
  • 批准号:
    8827201
  • 财政年份:
    2014
  • 资助金额:
    $ 34.05万
  • 项目类别:
Optogenetics for all: A general method for optical control of protein activity
所有人的光遗传学:蛋白质活性光学控制的通用方法
  • 批准号:
    8896827
  • 财政年份:
    2013
  • 资助金额:
    $ 34.05万
  • 项目类别:
Optogenetics for all: A general method for optical control of protein activity
所有人的光遗传学:蛋白质活性光学控制的通用方法
  • 批准号:
    9132820
  • 财政年份:
    2013
  • 资助金额:
    $ 34.05万
  • 项目类别:
Optogenetics for all: A general method for optical control of protein activity
所有人的光遗传学:蛋白质活性光学控制的通用方法
  • 批准号:
    8564060
  • 财政年份:
    2013
  • 资助金额:
    $ 34.05万
  • 项目类别:

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