FUS Protein Homeostasis in ALS

ALS 中的 FUS 蛋白稳态

基本信息

  • 批准号:
    10550115
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-10-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

Amyotrophic lateral sclerosis (ALS) is a poorly understood neurodegenerative disease with no effective treatment. ALS is connected with military service and veterans are at a higher risk of developing this debilitating disease. Mutations in several genes have been discovered to cause a subset of familial ALS, including copper- zinc superoxide dismutase (SOD1), Fused in Sarcoma (FUS), and TAR DNA-binding protein 43 (TDP-43). Studying familial ALS using the well-defined genetic models will provide critical insights into the disease pathology as well as novel targets for future therapeutic development. This project is focused on the RNA binding protein FUS that has been implicated in both familial and sporadic ALS. ALS-related mutations in FUS cause a liquid-liquid phase separation (LLPS) of the FUS protein, forming liquid droplets in vitro. In neurons, mutant FUS accumulates in the cytoplasm, forming ribonucleoprotein granules and inclusions, eventually leading to neurotoxicity. We recently identified cellular proteins in FUS- positive inclusions and a bioinformatics analysis revealed two previously unknown pathways affected by mutant FUS: protein translation and mRNA surveillance. We also demonstrated that ALS FUS mutations indeed suppressed protein translation and hyper-activated the nonsense-mediated decay (NMD) of mRNAs. Our overarching hypothesis is that the dysregulation of protein translation and mRNA nonsense-mediated decay contributes to FUS toxicity and motor neuron dysfunction. Since little is known about how the mutant FUS- induced dysregulation of protein translation and NMD cause toxicity in neurons, discoveries in this project will fill this knowledge gap and advance the field significantly. Three specific aims are designed to test the hypothesis. Aim 1 is to determine what properties of mutant FUS drive the dysregulation of protein translation and NMD. We will use different domain truncations of FUS to manipulate LLPS and examine the relationship between LLPS and mutant FUS dysregulation. In addition, we will manipulate RNA binding of FUS and test whether RNA binding is a significant contributor to mutant FUS dysfunction. We will also use FUS knockout models to examine whether FUS plays a role in in protein translation and NMD under physiological conditions. Aim 2 is to determine whether mutant FUS impairs translation of specific proteins and NMD of specific mRNAs. We will employ specialized proteomic and transcriptomic approaches to identify changes of nascent protein biosynthesis and mRNA turnover rate as a consequence of mutant FUS. Differentially altered proteins and mRNAs will be validated in animal models as well as iPSC and induced motor neurons derived from familial ALS patients. Results from these -omics approaches will be integrated to determine whether mutant FUS impairs specific molecular and cellular function and pathways. Aim 3 is to examine whether attenuation of NMD hyperactivity can restore protein translation and mitigate FUS neurotoxicity. We will use genetic and pharmacological approaches to attenuate NMD hyperactivity and determine whether the intervention can restore the balance and mitigate FUS toxicity in vitro and in vivo models. The proposed studies are highly innovative, both conceptually and technically. The proposal is based on a number of novel observations regarding the impact of ALS mutant FUS on protein translation and mRNA decay. The results from this project are expected to produce new mechanistic insights into FUS ALS, laying a foundation for future therapeutic development of new ALS treatment(s).
肌萎缩侧索硬化症(ALS)是一种了解甚少的神经退行性疾病, 治疗ALS与服兵役有关,退伍军人患这种使人衰弱的疾病的风险更高。 疾病已经发现几个基因的突变引起家族性ALS的一个子集,包括铜- 锌超氧化物歧化酶(SOD 1)、肉瘤融合蛋白(FUS)和TAR DNA结合蛋白43(TDP-43)。 使用定义明确的遗传模型研究家族性ALS将为该疾病提供重要的见解 病理学以及未来治疗发展的新靶点。 该项目的重点是RNA结合蛋白FUS,该蛋白与家族性和 散发性ALS。FUS中的ALS相关突变引起FUS蛋白的液-液相分离(LLPS), 在体外形成液滴。在神经元中,突变的FUS在细胞质中积累,形成核糖核蛋白 颗粒和内含物,最终导致神经毒性。我们最近在FUS中发现了细胞蛋白质- 阳性包涵体和生物信息学分析揭示了两个以前未知的途径受突变 FUS:蛋白质翻译和mRNA监测。我们还证明了ALS FUS突变确实 抑制蛋白质翻译并过度激活mRNA的无义介导的衰变(NMD)。我们 最重要的假设是,蛋白质翻译和mRNA无义介导的衰变的失调 导致FUS毒性和运动神经元功能障碍。因为我们对变异的FUS- 诱导的蛋白质翻译失调和NMD导致神经元毒性,该项目的发现将填补 这一知识差距,并推动该领域的显着。 设计了三个具体目标来检验这一假设。目的1是确定突变体的哪些特性 FUS驱动蛋白质翻译和NMD的失调。我们将使用不同的域截断FUS, 操纵LLPS并检查LLPS与突变型FUS失调之间的关系。此外,我们会 操纵FUS的RNA结合并测试RNA结合是否是突变FUS的显著贡献者 功能障碍我们还将使用FUS敲除模型来检查FUS是否在蛋白质翻译中起作用 和NMD。目的2是确定突变的FUS是否会损害 特异性蛋白质和特异性mRNA的NMD。我们将使用专门的蛋白质组学和转录组学 方法来确定新生蛋白质生物合成和mRNA周转率的变化,作为一个结果, 突变型FUS。差异改变的蛋白质和mRNA将在动物模型以及iPSC中验证, 来自家族性ALS患者的诱导运动神经元。这些组学方法的结果将是 整合,以确定突变FUS是否损害特定的分子和细胞功能和途径。目的 3是检查NMD过度活跃的减弱是否可以恢复蛋白质翻译并减轻FUS 神经毒性我们将使用遗传和药理学方法来减弱NMD多动症, 确定干预是否可以恢复平衡并减轻体外和体内模型中的FUS毒性。 拟议的研究在概念和技术上都具有很高的创新性。所涉提议主要是 关于ALS突变体FUS对蛋白质翻译和mRNA的影响, 腐烂该项目的结果有望对FUS ALS产生新的机理见解, 为未来开发新的ALS治疗方法奠定了基础。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Haining Zhu其他文献

Haining Zhu的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Haining Zhu', 18)}}的其他基金

BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10703154
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
RNA Surveillance and Protein Translation in FTD
FTD 中的 RNA 监测和蛋白质翻译
  • 批准号:
    10687846
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
RNA Surveillance and Protein Translation in FTD
FTD 中的 RNA 监测和蛋白质翻译
  • 批准号:
    10449486
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
RNA Surveillance and Protein Translation in FTD
FTD 中的 RNA 监测和蛋白质翻译
  • 批准号:
    10455737
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
FUS Protein Homeostasis in ALS
ALS 中的 FUS 蛋白稳态
  • 批准号:
    9892565
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
FUS Protein Homeostasis in ALS
ALS 中的 FUS 蛋白稳态
  • 批准号:
    10620292
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Role of FUS in ALS
FUS 在 ALS 中的作用
  • 批准号:
    8234739
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Role of FUS in ALS
FUS 在 ALS 中的作用
  • 批准号:
    8313863
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
PROTEOMICS CORE
蛋白质组学核心
  • 批准号:
    8360573
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Role of FUS in ALS
FUS 在 ALS 中的作用
  • 批准号:
    8449217
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了