Impact of mutant VPS35 on human dopaminergic neurons

突变体 VPS35 对人类多巴胺能神经元的影响

基本信息

  • 批准号:
    288892088
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    德国
  • 项目类别:
    Research Fellowships
  • 财政年份:
    2015
  • 资助国家:
    德国
  • 起止时间:
    2014-12-31 至 2016-12-31
  • 项目状态:
    已结题

项目摘要

The overall hypothesis in this application is that impaired cellular trafficking plays a key role in the pathogenesis of Parkinson disease (PD); and that this global insult will have more pronounced effects in more vulnerable neurons. PD is the second most common neurodegenerative disorder and pathologically associated with the death of midbrain DA neurons. These neurons are characterized by a unique anatomical complexity, which is combined with high bioenergetic demands due to intense trafficking processes and may make DA neurons particularly vulnerable to stress. Mutations in the gene vacuolar protein sorting 35 (VPS35) were recently linked to dominantly inherited PD, a rare monogenetic form that is clinically indistinguishable from idiopathic PD. VPS35 has been shown to regulate vesicle sorting and degradation. In a collaborative study between the applicant and the laboratory of the selected host institute, our teams showed that VPS35 binds and traffics excitatory neurotransmitter receptors and governs their surface levels and functional fate. The goal of this application is to extend our preliminary study and to establish and characterize a human DA neuronal model using patient-derived induced pluripotent stem cells (iPSCs) harboring a VPS35 mutation to examine the impact of this mutation. The following three specific aims will be addressed: (i) Establish a cell culture of human DA neurons derived from iPSC lines (patient and isogenic control) amenable to live-cell assays. These cultures will contain mature, identifiable DA neurons in co-culture with excitatory cortical neurons. (ii) Assess these neurons for morphological and physiological phenotypes. Axonal arborisation and neurite outgrowth of identified DA neurons will be assessed by confocal microscopy, and intrinsic excitability, channel function, and action potential firing will be assessed by whole cell patch-clamp technique. (iii) Basal and pharmacologically stimulated DA release will be measured by HPLC. In additional to novel pathophysiological insights into PD, the ultimate value of this project will be an extensively characterized unique model of human disease that is highly amenable to experimental manipulations and available for the screening of new therapeutic compounds.
本申请中的总体假设是受损的细胞运输在帕金森病(PD)的发病机制中起关键作用;并且这种整体损伤将在更脆弱的神经元中具有更显著的影响。PD是第二种最常见的神经退行性疾病,并且在病理上与中脑DA神经元的死亡相关。这些神经元的特征在于独特的解剖学复杂性,这与高生物能量需求相结合,由于激烈的贩运过程,并可能使DA神经元特别容易受到压力。基因vacuolar protein sorting 35(VPS 35)的突变最近与显性遗传性PD有关,这是一种罕见的单基因形式,在临床上与特发性PD无法区分。VPS 35已显示出调节囊泡分选和降解。在申请人和选定的主办机构的实验室之间的合作研究中,我们的团队表明,VPS 35结合和运输兴奋性神经递质受体,并控制它们的表面水平和功能命运。本申请的目标是扩展我们的初步研究,并使用携带VPS 35突变的患者来源的诱导多能干细胞(iPSC)建立和表征人类DA神经元模型,以检查该突变的影响。将解决以下三个具体目标:(i)建立来源于iPSC系(患者和同基因对照)的人DA神经元的细胞培养物,其适合于活细胞测定。这些培养物将含有与兴奋性皮质神经元共培养的成熟的、可识别的DA神经元。(ii)评估这些神经元的形态和生理表型。将通过共聚焦显微镜评估鉴定的DA神经元的轴突分支和神经突生长,并通过全细胞膜片钳技术评估内在兴奋性、通道功能和动作电位放电。(iii)将通过HPLC测量基础和多巴胺刺激的DA释放。除了对PD的新的病理生理学见解外,该项目的最终价值将是一种广泛表征的独特的人类疾病模型,该模型非常适合实验操作,并可用于筛选新的治疗化合物。

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 }}

Dr. Philip Seibler其他文献

Dr. Philip Seibler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 }}

相似国自然基金

拟南芥中新型腺苷酸激酶6(AK6)基因的克隆和功能研究
  • 批准号:
    31071075
  • 批准年份:
    2010
  • 资助金额:
    31.0 万元
  • 项目类别:
    面上项目
从离子通道蛋白TRPC6角度探讨突变podocin致足细胞损伤的分子机制
  • 批准号:
    30801250
  • 批准年份:
    2008
  • 资助金额:
    21.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Exploring mechanisms of Parkinson's disease-linked D620N VPS35 in rat models
在大鼠模型中探索帕金森病相关 D620N VPS35 的机制
  • 批准号:
    10445271
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Exploring mechanisms of Parkinson's disease-linked D620N VPS35 in rat models
在大鼠模型中探索帕金森病相关 D620N VPS35 的机制
  • 批准号:
    10202777
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Exploring mechanisms of Parkinson's disease-linked D620N VPS35 in rat models
在大鼠模型中探索帕金森病相关 D620N VPS35 的机制
  • 批准号:
    10656398
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Mechanisms of VPS35-Dependent Neurodegeneration in Parkinson's Disease
帕金森病中 VPS35 依赖性神经变性的机制
  • 批准号:
    9753383
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Mechanisms of VPS35-Dependent Neurodegeneration in Parkinson's Disease
帕金森病中 VPS35 依赖性神经变性的机制
  • 批准号:
    9975928
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Mechanisms of VPS35-Dependent Neurodegeneration in Parkinson's Disease
帕金森病中 VPS35 依赖性神经变性的机制
  • 批准号:
    10227170
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Characterization and Validation of Mouse VPS35 Model of Parkinson's Disease
帕金森病小鼠 VPS35 模型的表征和验证
  • 批准号:
    9316771
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
VPS35 D620N inhibits autophagy through disrupted hyaluronic acid-CD44 signaling
VPS35 D620N 通过破坏透明质酸-CD44 信号传导抑制自噬
  • 批准号:
    10226312
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
VPS35 D620N inhibits autophagy through disrupted hyaluronic acid-CD44 signaling
VPS35 D620N 通过破坏透明质酸-CD44 信号传导抑制自噬
  • 批准号:
    10415177
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
New Drosophila Model of VPS35 Parkinsonism
VPS35帕金森病的新果蝇模型
  • 批准号:
    8773498
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了