Methylglyoxal drives astrocyte senescence to mediate neurodegeneration in Alzheimer's disease

甲基乙二醛驱动星形胶质细胞衰老介导阿尔茨海默病的神经退行性变

基本信息

  • 批准号:
    10794538
  • 负责人:
  • 金额:
    $ 11.54万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-01 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

PARENT GRANT: PROJECT SUMMARY Senescent astrocytes and microglia, which accumulate with age and in patients with AD, contribute to neurodegeneration. A major gap in our knowledge is understanding the mechanisms that lead to astrocyte senescence. Our long-term goal is to define the molecular targets and therapeutic interventions that slow aging by inhibiting senescence and to determine their impact on neurodegenerative diseases. The overall objective in this application is to: 1) define the mechanisms by which the glycolytic by-product methylglyoxal (MGO) drives astrocyte senescence and 2) enhance the detoxification of MGO to mitigate astrocyte senescence and neurodegeneration in models of AD. Our central hypothesis is that MGO induces senescence in astrocytes, which secrete pro-inflammatory senescence-associated secretory phenotype (SASP) factors that cause the neurodegeneration associated with dementia and AD. The rationale of our hypothesis is based partly on the fact that astrocytes are known to be the metabolic workhorses of the brain and undertake glycolysis to provide neurons with lactate. Consequently, astrocytes produce more MGO and show increased activity of the MGO detoxifying pathways. We observe that MGO, which enhances macromolecular damage, causes senescence. Thus, strategies to detoxify MGO can provide novel approaches to lowering the risk of AD and related neurodegeneration in the elderly. We will test the hypothesis by pursuing the following Specific Aims: 1). Determine the mechanisms by which MGO drives senescence in human iPSC derived astrocytes; 2) Determine the mechanisms by which senescent astrocytes cause neuronal damage; and 3) Determine the role of the Trpa1 pathway in modulating MGO-induced senescence and AD pathology in mouse models. We will use iPSC derived astrocytes to determine the mechanisms by which MGO mediates senescence. Furthermore, we will use proteomics to define the SASP of MGO-induced senescent astrocytes and determine the effect of the SASP on iPSC-derived neurons carrying wild type and mutant alleles of tau using co-cultures. We will genetically and pharmacologically manipulate Trpa1 to detoxify MGO to test its effects on senescence and associated neurodegeneration in two mouse models of AD. We will combine the treatments to detoxify MGO and eliminate senescent cells to determine if they are working through the same pathways to inhibit neurodegeneration. The proposed research is innovative because it will determine a novel function for MGO, an endogenous metabolite produced during glycolysis, in driving astrocytic senescence and, thus, neurodegeneration. A key significance of this work will help us understand the link between metabolism, inflammation, and neurodegeneration. It will also pave the way to developing novel therapies for treating Alzheimer’s and related dementias based on reducing the presence or activity of senescent cells and by lowering MGO.
项目资助:项目总结 随着年龄的增长和AD患者体内衰老的星形胶质细胞和小胶质细胞的积累,有助于 神经变性我们知识的一个主要空白是理解导致星形胶质细胞 衰老我们的长期目标是确定分子靶点和治疗干预, 通过抑制衰老来衰老,并确定它们对神经退行性疾病的影响。整体 本申请的目的是:1)确定糖酵解副产物甲基乙二醛 (MGO)驱动星形胶质细胞衰老和2)增强MGO的解毒以减轻星形胶质细胞 衰老和神经退行性变。我们的中心假设是MGO诱导衰老 在分泌促炎衰老相关分泌表型(SASP)因子的星形胶质细胞中, 导致痴呆和AD相关的神经变性。我们的假设是基于 部分是因为星形胶质细胞被认为是大脑的代谢主力, 糖酵解为神经元提供乳酸。因此,星形胶质细胞产生更多的MGO,并表现出增加的 MGO解毒途径的活性。我们观察到,MGO,这增强了大分子损伤, 导致衰老因此,解毒MGO的策略可以提供降低AD风险的新方法 以及与之相关的老年神经退行性疾病我们将通过以下具体步骤来检验假设: 目的:1)。确定MGO驱动人iPSC衍生星形胶质细胞衰老的机制; 2) 确定衰老星形胶质细胞引起神经元损伤的机制; 3)确定星形胶质细胞在神经元损伤中的作用。 Trpa 1通路在调节小鼠模型中MGO诱导的衰老和AD病理学中的作用。我们将 使用iPSC衍生的星形胶质细胞来确定MGO介导衰老的机制。 此外,我们将使用蛋白质组学来定义MGO诱导的衰老星形胶质细胞的SASP,并确定 使用共培养物,SASP对携带tau的野生型和突变体等位基因的iPSC衍生的神经元的作用。 我们将通过基因和生物学方法操纵Trpa 1来解毒MGO,以测试其对衰老的影响。 和相关的神经变性。我们将联合收割机的治疗, MGO和消除衰老细胞,以确定它们是否通过相同的途径抑制 神经变性拟议的研究具有创新性,因为它将确定MGO的新功能, 一种糖酵解过程中产生的内源性代谢物,驱动星形胶质细胞衰老,因此, 神经变性这项工作的一个关键意义将帮助我们了解新陈代谢之间的联系, 炎症和神经变性。它还将为开发新的治疗方法铺平道路 基于减少衰老细胞的存在或活性, 降低MGO。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Immune checkpoint inhibitors as senolytic agents.
免疫检查点抑制剂作为抗衰老剂。
  • DOI:
    10.1038/s41422-022-00761-4
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    44.1
  • 作者:
    Singh,Parminder;Kapahi,Pankaj;vanDeursen,JanM
  • 通讯作者:
    vanDeursen,JanM
Comprehensive proteomic quantification of bladder stone progression in a cystinuric mouse model using data-independent acquisitions.
  • DOI:
    10.1371/journal.pone.0250137
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
  • 通讯作者:
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Pankaj Kapahi其他文献

Pankaj Kapahi的其他文献

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{{ truncateString('Pankaj Kapahi', 18)}}的其他基金

Targeting conserved diet-responsive transcriptional networks in neurons to slow neurodegeneration in Alzheimer's disease
针对神经元中保守的饮食反应转录网络以减缓阿尔茨海默病的神经退行性变
  • 批准号:
    10222430
  • 财政年份:
    2021
  • 资助金额:
    $ 11.54万
  • 项目类别:
Methylglyoxal drives astrocyte senescence to mediate neurodegeneration in Alzheimer's disease
甲基乙二醛驱动星形胶质细胞衰老介导阿尔茨海默病的神经退行性变
  • 批准号:
    10044138
  • 财政年份:
    2020
  • 资助金额:
    $ 11.54万
  • 项目类别:
Methylglyoxal drives astrocyte senescence to mediate neurodegeneration in Alzheimer's disease
甲基乙二醛驱动星形胶质细胞衰老介导阿尔茨海默病的神经退行性变
  • 批准号:
    10633000
  • 财政年份:
    2020
  • 资助金额:
    $ 11.54万
  • 项目类别:
Methylglyoxal drives astrocyte senescence to mediate neurodegeneration in Alzheimer's disease
甲基乙二醛驱动星形胶质细胞衰老介导阿尔茨海默病的神经退行性变
  • 批准号:
    10222563
  • 财政年份:
    2020
  • 资助金额:
    $ 11.54万
  • 项目类别:
Methylglyoxal drives astrocyte senescence to mediate neurodegeneration in Alzheimer's disease
甲基乙二醛驱动星形胶质细胞衰老介导阿尔茨海默病的神经退行性变
  • 批准号:
    10672363
  • 财政年份:
    2020
  • 资助金额:
    $ 11.54万
  • 项目类别:
Methylglyoxal drives astrocyte senescence to mediate neurodegeneration in Alzheimer's disease
甲基乙二醛驱动星形胶质细胞衰老介导阿尔茨海默病的神经退行性变
  • 批准号:
    10456805
  • 财政年份:
    2020
  • 资助金额:
    $ 11.54万
  • 项目类别:
Advanced glycation endproducts (AGEs) as metabolic by-products that mediate neurodegeneration.
晚期糖基化终产物 (AGE) 作为介导神经退行性变的代谢副产物。
  • 批准号:
    10417096
  • 财政年份:
    2019
  • 资助金额:
    $ 11.54万
  • 项目类别:
Advanced glycation endproducts (AGEs) as metabolic by-products that mediate neurodegeneration.
晚期糖基化终产物 (AGE) 作为介导神经退行性变的代谢副产物。
  • 批准号:
    10624982
  • 财政年份:
    2019
  • 资助金额:
    $ 11.54万
  • 项目类别:
Advanced glycation endproducts (AGEs) as metabolic by-products that mediate neurodegeneration.
晚期糖基化终产物 (AGE) 作为介导神经退行性变的代谢副产物。
  • 批准号:
    10017128
  • 财政年份:
    2019
  • 资助金额:
    $ 11.54万
  • 项目类别:
Advanced glycation endproducts (AGEs) as metabolic by-products that mediate neurodegeneration.
晚期糖基化终产物 (AGE) 作为介导神经退行性变的代谢副产物。
  • 批准号:
    10213648
  • 财政年份:
    2019
  • 资助金额:
    $ 11.54万
  • 项目类别:

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