Mechanistic analysis of axonal transport defects in neurodegenerative disease

神经退行性疾病轴突运输缺陷的机制分析

基本信息

  • 批准号:
    9896888
  • 负责人:
  • 金额:
    $ 45.83万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-04-01 至 2021-03-31
  • 项目状态:
    已结题

项目摘要

Project Summary Mutations in cytoplasmic dynein or its activator dynactin are causative for neuronal diseases including heritable forms of motor neuron degeneration and Charcot­Marie­Tooth disease. More broadly, we know that defects in dynein­driven functions such as retrograde axonal transport are involved in the pathogenic mechanisms of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Huntington’s, and Alzheimer’s. However, the specific mechanisms involved remain unclear. Dynein is a pleiotropic cellular motor with multiple distinct roles in the neuron. Here we will focus on the hypothesis that defects in the dynein­driven retrograde transport of degradative organelles including lysosomes and autophagosomes are major contributors to the axonal degeneration that characterize these diseases. The goal of this proposal is to understand the specific mechanisms linking defects in dynein function to neurodegeneration, focusing on the following three aims: (1) How is retrograde axonal transport altered during neurodegeneration? We hypothesize that pathological alterations in the JNK and Cdk5 pathways lead to the dysregulation of opposing microtubule motors during axonal transport. We will test this hypothesis using quantitative live cell imaging of vesicular transport in primary neurons from multiple models of ALS. Then, we will mechanistically dissect how kinase mis­regulation affects motor function using in vitro reconstitution approaches with single molecule resolution. These studies will test the model that a disruption in the coordination of oppositely­oriented motors is the primary defect leading to altered transport along the axon. (2) What are the pathways for autophagosome biogenesis and cargo­loading in the neuron? We hypothesize that autophagy in the neuron follows a stereotypical and spatially regulated pathway that is required to maintain cellular homeostasis. We will examine autophagosome biogenesis and cargo­loading in primary sensory and motor neurons using quantitative live cell imaging, focusing on the roles of dynein and optineurin. Then we will determine how this pathway responds to cellular stressors, to address the hypothesis that this pathway has a limited ability to up­regulate in response to cellular stress. (3) How do defects in dynein­driven autophagy lead to degeneration of the axon? We hypothesize that the active, dynein­driven transport of autophagosomes is tightly linked to function, and that defects in transport will lead to defective degradation of aging organelles and aggregated proteins. We will use live imaging and biochemical and cellular assays to determine how defects in autophagosome transport along the axon contribute to neurodegeneration and how distinct dynein mutations differentially perturb cellular functions, leading to disparate clinical manifestations. Mutations in cytoplasmic dynein are sufficient to cause human neurodegenerative diseases including spinal muscular atrophy (SMA­LED) and Charcot­Marie­Tooth disease (Type 2O), but the mechanisms involved remain to be determined. Progress on these aims should offer new opportunities for therapeutic approaches or clinical intervention.
项目总结

项目成果

期刊论文数量(27)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
What Doesn't Kill You Makes You Stronger.
那些杀不死你的会让你变得更强大。
  • DOI:
    10.1016/j.devcel.2018.11.003
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    11.8
  • 作者:
    Stavoe,AndreaKH;Holzbaur,ErikaLF
  • 通讯作者:
    Holzbaur,ErikaLF
Vesicular degradation pathways in neurons: at the crossroads of autophagy and endo-lysosomal degradation
  • DOI:
    10.1016/j.conb.2019.01.005
  • 发表时间:
    2019-08-01
  • 期刊:
  • 影响因子:
    5.7
  • 作者:
    Boecker, C. Alexander;Holzbaur, Erika L. F.
  • 通讯作者:
    Holzbaur, Erika L. F.
Axonal autophagy: Mini-review for autophagy in the CNS.
  • DOI:
    10.1016/j.neulet.2018.03.025
  • 发表时间:
    2019-04-01
  • 期刊:
  • 影响因子:
    2.5
  • 作者:
    Stavoe AKH;Holzbaur ELF
  • 通讯作者:
    Holzbaur ELF
ALS- and FTD-associated missense mutations in TBK1 differentially disrupt mitophagy.
Neuroligin 1 is dynamically exchanged at postsynaptic sites.
{{ 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 }}

Erika L Holzbaur其他文献

Erika L Holzbaur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('Erika L Holzbaur', 18)}}的其他基金

Molecular Mechanisms of Axonal Transport and Organelle Dynamics
轴突运输和细胞器动力学的分子机制
  • 批准号:
    9922337
  • 财政年份:
    2018
  • 资助金额:
    $ 45.83万
  • 项目类别:
Molecular Mechanisms of Axonal Transport and Organelle Dynamics
轴突运输和细胞器动力学的分子机制
  • 批准号:
    10621591
  • 财政年份:
    2018
  • 资助金额:
    $ 45.83万
  • 项目类别:
Molecular Mechanisms of Axonal Transport and Organelle Dynamics
轴突运输和细胞器动力学的分子机制
  • 批准号:
    10155504
  • 财政年份:
    2018
  • 资助金额:
    $ 45.83万
  • 项目类别:
Mechanistic analysis of axonal transport defects in neurodegenerative disease
神经退行性疾病轴突运输缺陷的机制分析
  • 批准号:
    9617503
  • 财政年份:
    2018
  • 资助金额:
    $ 45.83万
  • 项目类别:
Molecular Mechanisms of Axonal Transport and Organelle Dynamics
轴突运输和细胞器动力学的分子机制
  • 批准号:
    10397408
  • 财政年份:
    2018
  • 资助金额:
    $ 45.83万
  • 项目类别:
Mechanistic analysis of axonal transport defects in motor neuron degenerative dis
运动神经元退行性疾病轴突运输缺陷的机制分析
  • 批准号:
    7524459
  • 财政年份:
    2008
  • 资助金额:
    $ 45.83万
  • 项目类别:
Mechanistic analysis of axonal transport defects in motor neuron degenerative dis
运动神经元退行性疾病轴突运输缺陷的机制分析
  • 批准号:
    8270484
  • 财政年份:
    2008
  • 资助金额:
    $ 45.83万
  • 项目类别:
Dynamics of Axonal Autophagy in Neurons
神经元轴突自噬的动力学
  • 批准号:
    10223588
  • 财政年份:
    2008
  • 资助金额:
    $ 45.83万
  • 项目类别:
Dynamics of Axonal Autophagy in Neurons
神经元轴突自噬的动力学
  • 批准号:
    10610929
  • 财政年份:
    2008
  • 资助金额:
    $ 45.83万
  • 项目类别:
Mechanistic analysis of axonal transport defects in motor neuron degenerative dis
运动神经元退行性疾病轴突运输缺陷的机制分析
  • 批准号:
    8079649
  • 财政年份:
    2008
  • 资助金额:
    $ 45.83万
  • 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:
    $ 45.83万
  • 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:
    $ 45.83万
  • 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:
    $ 45.83万
  • 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:
    $ 45.83万
  • 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:
    $ 45.83万
  • 项目类别:
    Standard Grant
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:
    $ 45.83万
  • 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:
    $ 45.83万
  • 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:
    $ 45.83万
  • 项目类别:
    EU-Funded
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:
    $ 45.83万
  • 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:
    $ 45.83万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了