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:
    10044138
  • 负责人:
  • 金额:
    $ 48.5万
  • 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 2025-07-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY / ABSTRACT 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.
项目摘要 /摘要 随着年龄的增长和AD患者积累的衰老星形胶质细胞和小胶质细胞,有助于 神经变性。我们知识上的一个主要差距是了解导致星形胶质细胞的机制 感应。我们的长期目标是定义缓慢衰老的分子靶标和治疗干预措施 通过抑制感应并确定其对神经退行性疾病的影响。总体目标 该应用是:1)定义糖酵解副产物甲基乙二醇(MGO)驱动器的机制 星形胶质细胞的感应和2)增强MGO的排毒以减轻星形胶质细胞的感应和 AD模型中的神经变性。我们的中心假设是MGO诱导星形胶质细胞的感受, 哪个分泌促炎感应相关的秘书表型(SASP)因素 与痴呆和AD相关的神经变性。我们假设的理由部分基于 事实认为,星形胶质细胞是大脑的代谢工作主场,并进行糖酵解以提供 乳酸神经元。因此,星形胶质细胞产生更多的MGO并显示出MGO的活动增加 解毒途径。我们观察到,MGO增强了大分子损害,会导致衰老。 这是对MGO排毒的策略可以提供新颖的方法来降低AD和相关的风险 最古老的神经变性。我们将通过追求以下特定目的来检验假设:1)。 确定MGO在人IPSC衍生的星形胶质细胞中驱动感受的机制; 2)确定 感觉星形胶质细胞引起神经元损害的机制; 3)确定TRPA1的作用 在小鼠模型中调节MGO诱导的感应和AD病理学的途径。我们将使用IPSC 衍生的星形胶质细胞确定MGO介导衰老的机制。此外,我们会的 使用蛋白质组学来定义MGO诱导的感官星形胶质细胞的SASP并确定SASP的效果 在IPSC衍生的神经元上,使用共培养物携带Tau的野生型和突变等位基因。我们将从遗传上和 药理学操纵TRPA1以对MGO排毒,以测试其对感应和相关的影响 AD的两个小鼠模型中的神经变性。我们将结合使用以排毒MGO并消除的治疗方法 感觉细胞确定它们是否正在通过相同的途径来抑制神经退行性。这 拟议的研究具有创新性,因为它将确定MGO的新功能,一种内源代谢物 在糖酵解过程中产生,在驱动星形胶质细胞感应中,从而在神经变性中产生。一个 这项工作的关键意义将有助于我们了解新陈代谢,创新和 神经变性。它还将为开发新颖的治疗阿尔茨海默氏症和相关疗法铺平道路 痴呆基于降低感觉细胞的存在或通过降低MGO的存在或活性。

项目成果

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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:
    $ 48.5万
  • 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:
    10794538
  • 财政年份:
    2020
  • 资助金额:
    $ 48.5万
  • 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:
    $ 48.5万
  • 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:
    $ 48.5万
  • 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:
    $ 48.5万
  • 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:
    $ 48.5万
  • 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:
    $ 48.5万
  • 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:
    $ 48.5万
  • 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:
    $ 48.5万
  • 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:
    $ 48.5万
  • 项目类别:

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  • 批准号:
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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:
    $ 48.5万
  • 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:
    $ 48.5万
  • 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:
    $ 48.5万
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