Myeloid cells, aging and the metabolic syndrome

骨髓细胞、衰老和代谢综合征

基本信息

  • 批准号:
    8702069
  • 负责人:
  • 金额:
    $ 19.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-08-01 至 2016-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Inflammation contributes to metabolic syndrome, including insulin resistance and atherosclerosis. Further, metabolic syndrome represents a risk factor for age-related dementias. This proposal focuses on the role of MyD88, required for signaling from cytokine and Toll Like Receptors. We showed that selective deletion of MyD88 from myeloid cells virtually eliminated diet-induced metabolic syndrome in obese mice. Here we extend this research to effects of inflammatory signaling for age-related cognitive decline in aging obese mice with or without metabolic syndrome. The present proposal addresses the hypothesis that deleting MyD88 from all CD11b+ myeloid cells will ameliorate age-related cognitive impairment in mice with obesity but without metabolic syndrome. Furthermore, we propose that selective deletion of MyD88 from microglia will also reduce age-related cognitive impairment in mice with metabolic syndrome, without affecting the systemic syndrome. Importantly, MyD88 appears functionally orthologous in humans and mice, and its absence does not cause unacceptable immunodeficiency suggesting the pathway is potentially druggable. The specific aims are: 1. Establish whether ameliorating metabolic syndrome in MyD88fl/fl::CD11bCre mice on high-fat diet (HFD) is associated with improvement of age-related cognitive change. MyD88fl/fl::CD11bCre mice will be placed on HFD or chow and undergo serial behavior testing as well as hippocampal long-term potentiation (LTP). Pathological analyses of peripheral and CNS tissues will be performed. These data will address whether declining cognition is ameliorated in aging mice fed HFD by blocking innate immune reactions of myeloid cells and reducing metabolic syndrome systemically. 2. Determine if reduced microglial reaction in tamoxifen-injected MyD88fl/fl::CX3CR1(ER)-Cre mice on high-fat diet (HFD) improves age-related cognitive change. We anticipate that MyD88fl/fl::CD11bCre mice lacking myeloid-cell MyD88 will show improved age-related cognition as compared to controls. The mechanisms however could be exerted either systemically, in the CNS or both. The CX3CR1(ER)-Cre driver efficiently deletes 'floxed' targets from CX3CR1+ cells, and recombination is highly-selective for microglia by about one month after induction. MyD88fl/fl::CX3CR1(ER)- Cre mice will receive tamoxifen to induce recombination and will be placed on HFD or chow. Mice will be subjected to serial behavior testing and hippocampal LTP as in Aim 1. Focused pathological and immunohistochemical analyses of the peripheral and CNS tissues will be performed. These data will address whether declining cognition in aging mice is ameliorated by blocking innate immunity in microglia despite systemic metabolic syndrome. Data from these experiments will contribute to our knowledge of the systemic and CNS mechanisms by which metabolic syndrome-associated inflammation worsens cognitive function in aging individuals and will identify salient peripheral and CNS treatment targets.
描述(由申请人提供):炎症会导致代谢综合征,包括胰岛素抵抗和动脉粥样硬化。此外,代谢综合征是年龄相关性痴呆的危险因素。该提案重点关注 MyD88 的作用,它是细胞因子和 Toll 样受体信号传导所需的。我们发现,从骨髓细胞中选择性删除 MyD88 实际上消除了肥胖小鼠饮食诱导的代谢综合征。在这里,我们将这项研究扩展到炎症信号传导对患有或不患有代谢综合征的衰老肥胖小鼠中与年龄相关的认知能力下降的影响。目前的提议提出了这样一个假设:从所有 CD11b+ 骨髓细胞中删除 MyD88 将改善肥胖但无代谢综合征的小鼠与年龄相关的认知障碍。此外,我们提出,从小胶质细胞中选择性删除 MyD88 也将减少患有代谢综合征的小鼠与年龄相关的认知障碍,而不影响全身综合征。重要的是,MyD88 在人类和小鼠中表现出功能直系同源,并且它的缺失不会导致不可接受的免疫缺陷,表明该途径可能是可药物化的。具体目标是: 1. 确定高脂饮食 (HFD) MyD88fl/fl::CD11bCre 小鼠代谢综合征的改善是否与年龄相关认知变化的改善相关。 MyD88fl/fl::CD11bCre 小鼠将被置于 HFD 或食物中,并接受系列行为测试以及海马长时程增强 (LTP)。将进行外周和中枢神经系统组织的病理分析。这些数据将探讨是否可以通过阻断骨髓细胞的先天免疫反应和系统性减少代谢综合征来改善喂食 HFD 的衰老小鼠的认知能力下降。 2. 确定注射他莫昔芬并接受高脂饮食 (HFD) 的 MyD88fl/fl::CX3CR1(ER)-Cre 小鼠中小胶质细胞反应的减少是否会改善与年龄相关的认知变化。我们预计,与对照组相比,缺乏髓样细胞 MyD88 的 MyD88fl/fl::CD11bCre 小鼠将表现出与年龄相关的认知能力的改善。然而,这些机制可以在全身、中枢神经系统或两者中发挥作用。 CX3CR1(ER)-Cre 驱动程序可有效删除 CX3CR1+ 细胞中的“floxed”靶标,并且在诱导后约一个月内重组对小胶质细胞具有高度选择性。 MyD88fl/fl::CX3CR1(ER)-Cre 小鼠将接受他莫昔芬以诱导重组,并将被置于 HFD 或食物中。如目标 1 所示,将对小鼠进行一系列行为测试和海马 LTP。将对外周和 CNS 组织进行集中的病理学和免疫组织化学分析。这些数据将解决老年小鼠认知能力下降是否可以通过阻断小胶质细胞的先天免疫来改善,尽管存在全身代谢综合征。这些实验的数据将有助于我们了解代谢综合征相关炎症使老年人认知功能恶化的全身和中枢神经系统机制,并将确定显着的外周和中枢神经系统治疗目标。

项目成果

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Xiaoxia Li其他文献

Xiaoxia Li的其他文献

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{{ truncateString('Xiaoxia Li', 18)}}的其他基金

Core B: Animal Model and Immunotyping Core
核心 B:动物模型和免疫分型核心
  • 批准号:
    10493942
  • 财政年份:
    2022
  • 资助金额:
    $ 19.81万
  • 项目类别:
IL-17-driven mechanisms for tumor progression and resistance to therapies
IL-17 驱动的肿瘤进展和治疗耐药机制
  • 批准号:
    10493940
  • 财政年份:
    2022
  • 资助金额:
    $ 19.81万
  • 项目类别:
The role of TRAF4 E3 ligase in IL-25-mediated allergic asthma
TRAF4 E3 连接酶在 IL-25 介导的过敏性哮喘中的作用
  • 批准号:
    10112955
  • 财政年份:
    2020
  • 资助金额:
    $ 19.81万
  • 项目类别:
GSDMD-dependent IL-1 signaling in intestinal inflammation
肠道炎症中 GSDMD 依赖性 IL-1 信号传导
  • 批准号:
    10024455
  • 财政年份:
    2020
  • 资助金额:
    $ 19.81万
  • 项目类别:
The role of TRAF4 E3 ligase in IL-25-mediated allergic asthma
TRAF4 E3 连接酶在 IL-25 介导的过敏性哮喘中的作用
  • 批准号:
    9885028
  • 财政年份:
    2020
  • 资助金额:
    $ 19.81万
  • 项目类别:
IRAKM and Mincle in ALD
IRAKM 和 Mincle 在 ALD 中
  • 批准号:
    9067893
  • 财政年份:
    2015
  • 资助金额:
    $ 19.81万
  • 项目类别:
IRAKM and Mincle in ALD
IRAKM 和 Mincle 在 ALD 中
  • 批准号:
    8912063
  • 财政年份:
    2015
  • 资助金额:
    $ 19.81万
  • 项目类别:
Myeloid cells, aging and the metabolic syndrome
骨髓细胞、衰老和代谢综合征
  • 批准号:
    8611557
  • 财政年份:
    2013
  • 资助金额:
    $ 19.81万
  • 项目类别:
Molecular mechanisms of IL-1R-TLR mediated signaling
IL-1R-TLR介导信号传导的分子机制
  • 批准号:
    8242732
  • 财政年份:
    2011
  • 资助金额:
    $ 19.81万
  • 项目类别:
Molecular and Cellular Mechanisms of IL-17 Signaling
IL-17 信号传导的分子和细胞机制
  • 批准号:
    8453438
  • 财政年份:
    2011
  • 资助金额:
    $ 19.81万
  • 项目类别:

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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。
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