Molecular impact of endolysosomal dysfunction on neuron-glia communication pathways

内溶酶体功能障碍对神经元-胶质细胞通讯途径的分子影响

基本信息

  • 批准号:
    10538113
  • 负责人:
  • 金额:
    $ 6.72万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-29 至 2025-04-28
  • 项目状态:
    未结题

项目摘要

Project Abstract Alzheimer’s disease (AD) is a neurodegenerative disease and the most common form of dementia worldwide. Despite decades of research, there are few therapies that can delay or prevent AD progression. Retrograde trafficking through retromer-dependent cargo recognition has emerged as a critical cellular process that is mutated or disrupted in patients with AD and other forms of dementia. Conditional knockout of retromer genes in neurons leads to increased secretion of Tau and Amyloid β (Aβ), hallmark protein pathologies linked to AD. This milieu of neuronal-secreted factors leads to inflammation in microglia and astrocytes, two glial cell types thought to influence the progression of neurodegeneration. In this proposal, I aim to study the cascade of events linking neuronal retromer disruption to glial inflammation, characterizing the specific cell state changes involved, and identify the key factors that mediate this effect. I will address this aim using genetically engineered stem cell- derived models of human neurons, microglia, and astrocytes. Microglia also express retromer components and upregulate these factors in AD, yet there are few studies of retromer function specifically in microglia. In Aim 2 I will therefore explore the effects of retromer-related mutations specifically on microglia in the context of early aging in mice, a comparable time point to when dementia manifests in patients with these mutations. I will additionally utilize stem cell models to dissect the functional and signaling changes that are induced in microglia with retromer disruption. Finally, although there have been several studies looking at the effects of retromer on specific receptors, little is known about the systems-level effects of retromer mutations on protein trafficking to the endosomes. To identify retromer-dependent signaling pathways that may be pathogenic, I have developed novel proteomics tools to quantify endosomal proteome changes and will use these tools to compare the effects of different retromer mutations on neuronal and microglial endosomes. The ultimate goal is to understand how retromer disruption affects brain cell states and leads to pathogenic signaling changes.
项目摘要 阿尔茨海默病 (AD) 是一种神经退行性疾病,也是全世界最常见的痴呆症。 尽管进行了数十年的研究,但很少有疗法可以延缓或预防 AD 进展。逆行 通过依赖逆转录酶的货物识别进行贩运已成为一个关键的细胞过程, AD 和其他形式的痴呆症患者体内的突变或破坏。条件性敲除retromer基因 神经元中的 Tau 蛋白和 β 淀粉样蛋白 (Aβ) 分泌增加,这是与 AD 相关的标志性蛋白质病理。 这种神经元分泌因子的环境会导致小胶质细胞和星形胶质细胞(两种胶质细胞类型)的炎症 被认为影响神经退行性变的进展。在这个提案中,我的目标是研究一系列事件 将神经元逆转录酶破坏与神经胶质炎症联系起来,描述所涉及的特定细胞状态变化, 并确定介导这种影响的关键因素。我将使用基因工程干细胞来实现这个目标- 人类神经元、小胶质细胞和星形胶质细胞的衍生模型。小胶质细胞还表达逆转录酶成分 在 AD 中上调这些因子,但很少有针对小胶质细胞中逆转录酶功能的研究。目标 2 I 因此,我们将在早期的背景下探讨逆转录酶相关突变对小胶质细胞的影响。 小鼠的衰老,与携带这些突变的患者出现痴呆症的时间点相当。我会 另外利用干细胞模型来剖析小胶质细胞诱导的功能和信号传导变化 与逆转录酶破坏。最后,尽管已经有几项研究探讨了逆转录酶对 特定受体,关于逆转录酶突变对蛋白质运输的系统水平影响知之甚少。 内体。为了识别可能致病的逆转录酶依赖性信号通路,我开发了 新颖的蛋白质组学工具可量化内体蛋白质组变化,并将使用这些工具来比较效果 神经元和小胶质细胞内体上不同逆转录体突变的研究。最终目标是了解如何 逆转录酶破坏会影响脑细胞状态并导致致病信号变化。

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 }}

Nader Francis Morshed其他文献

Nader Francis Morshed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 }}

相似海外基金

Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
  • 批准号:
    495182
  • 财政年份:
    2023
  • 资助金额:
    $ 6.72万
  • 项目类别:
Parkinson's disease and aging affect neural activation during continuous gait alterations to the split-belt treadmill: An [18F] FDG PET Study.
帕金森病和衰老会影响分体带跑步机连续步态改变期间的神经激活:[18F] FDG PET 研究。
  • 批准号:
    400097
  • 财政年份:
    2019
  • 资助金额:
    $ 6.72万
  • 项目类别:
The elucidation of the mechanism by which intestinal epithelial cells affect impaired glucose tolerance during aging
阐明衰老过程中肠上皮细胞影响糖耐量受损的机制
  • 批准号:
    19K09017
  • 财政年份:
    2019
  • 资助金额:
    $ 6.72万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Does aging of osteocytes adversely affect bone metabolism?
骨细胞老化会对骨代谢产生不利影响吗?
  • 批准号:
    18K09531
  • 财政年份:
    2018
  • 资助金额:
    $ 6.72万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Links between affect, executive function, and prefrontal structure in aging: A longitudinal analysis
衰老过程中情感、执行功能和前额叶结构之间的联系:纵向分析
  • 批准号:
    9766994
  • 财政年份:
    2018
  • 资助金额:
    $ 6.72万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9320090
  • 财政年份:
    2017
  • 资助金额:
    $ 6.72万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    10166936
  • 财政年份:
    2017
  • 资助金额:
    $ 6.72万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9761593
  • 财政年份:
    2017
  • 资助金额:
    $ 6.72万
  • 项目类别:
Experimental Model of Depression in Aging: Insomnia, Inflammation, and Affect Mechanisms
衰老过程中抑郁症的实验模型:失眠、炎症和影响机制
  • 批准号:
    9925164
  • 财政年份:
    2016
  • 资助金额:
    $ 6.72万
  • 项目类别:
Experimental Model of Depression in Aging: Insomnia, Inflammation, and Affect Mechanisms
衰老过程中抑郁症的实验模型:失眠、炎症和影响机制
  • 批准号:
    9345997
  • 财政年份:
    2016
  • 资助金额:
    $ 6.72万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了