Dietary sodium, neurovascular dysfunction and cerebrovascular risk

膳食钠、神经血管功能障碍和脑血管风险

基本信息

  • 批准号:
    10298081
  • 负责人:
  • 金额:
    $ 59.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-12-01 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

Salt consumption across the world greatly exceeds minimal requirements, and excessive dietary salt has emerged as a powerful risk factor for cognitive impairment and dementia. Increasing evidence indicates that a high salt diet (HSD) is harmful to brain health independently of the increase in blood pressure associated with HSD in salt-sensitive individuals. Unfortunately, public health efforts to curb salt intake have been futile and dietary salt consumption continues to rise worldwide. The long-term goal of this research program is to elucidate the mechanisms by which HSD is injurious to cognitive health and to develop new approaches to counteract it. During the previous funding period, we have demonstrated that HSD in mice leads to a reduction in cerebral blood flow (CBF) and cognitive impairment through suppression of endothelial nitric oxide (NO) production. These effects are mediated by a subclass of T-helper lymphocytes (Th17) in the small intestine that increases circulating levels of the cytokine IL17. IL17, in turn, leads to inhibition of endothelial NO synthase (eNOS) in cerebral endothelial cells. The resulting deficit in endothelial NO induces cognitive impairment through neuronal accumulation of hyperphosphorylated tau, a microtubule associated protein linked to Alzheimer’s disease and related dementias. However, the factors triggering the production IL17 in the gut, the cellular localization of the IL17 receptors inducing eNOS inhibition, and the role of the CBF reduction in tau accumulation remain to be established. This renewal application seeks to advance the mechanistic understanding of the cognitive effects of HSD by testing the following novel hypotheses: (a) HSD triggers distinct innate and adaptive immune responses in the gut through the microbiota, (b) the resulting increase in circulating IL17 acts on cerebral endothelial IL17 receptors to inhibit eNOS through downregulation of the eNOS regulatory protein striatin and, (c) the increased leukocyte adhesion resulting from the NO deficit leads to microvascular occlusions (capillary stalling) which promote tau accumulation in brain by reducing its microvascular clearance into the bloodstream. We will use a well-characterized model of HSD in young and old males and female mice and state-of-the- art approaches to examine gut-brain immune interactions, microvascular function, hyperphosphorylated tau, and cognitive deficits. These studies advance the understanding of the pathobiology of excessive dietary salt at the cellular and molecular levels and may lead to new approaches to mitigate its harmful effects on brain health that lead to cognitive impairment.
世界各地的食盐消费量大大超过了最低要求,而且饮食过度 盐分已经成为认知障碍和痴呆症的一个强大的风险因素。渐增 有证据表明,高盐饮食(HSD)对大脑健康有害,独立于 盐敏感人群中与HSD相关的血压升高。不幸的是,公众 控制食盐摄入量的健康努力一直是徒劳的,食盐消费量继续上升 全世界。这项研究计划的长期目标是阐明 HSD对认知健康有害,并开发新的方法来抵消它。在.期间 在之前的资助期间,我们已经证明了HSD在小鼠身上会导致大脑中 血流(CBF)与内皮型一氧化氮(NO)抑制引起的认知损害 制作。这些效应是由小鼠T辅助淋巴细胞亚类(Th17)介导的 增加循环中细胞因子IL17水平的肠道。白介素17反过来又导致抑制 脑内皮细胞内皮型一氧化氮合酶(ENOS)的表达。由此导致的内皮细胞缺陷 一氧化氮通过过度磷酸化的tau蛋白在神经元中积聚而导致认知功能障碍 与阿尔茨海默病和相关痴呆有关的微管相关蛋白。然而, 肠道产生IL-17的触发因素及IL-17受体的细胞定位 诱导eNOS抑制,CBF降低在tau蓄积中的作用仍有待进一步研究 已经成立了。这项续期申请旨在推进对 HSD的认知效应通过检验以下新的假设:(A)HSD触发独特的先天 和肠道中通过微生物区系的适应性免疫反应,(B)由此导致的 循环IL-17通过作用于脑内皮细胞IL-17受体抑制eNOS ENOS调节蛋白纹状体蛋白下调,以及(C)白细胞黏附增加 由于NO缺乏导致微血管闭塞(毛细血管停滞),从而促进 通过减少进入血液的微血管清除量,tau在大脑中积累。我们会 在年轻的和老年的雄性和雌性小鼠中使用具有良好特征的HSD模型,并且 ART方法检查肠道-大脑免疫相互作用,微血管功能, 过度磷酸化的tau和认知缺陷。这些研究促进了对 在细胞和分子水平上过量饮食盐的病理生物学,并可能导致新的 减轻其对大脑健康的有害影响的方法,这些有害影响导致认知障碍。

项目成果

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Costantino Iadecola其他文献

Costantino Iadecola的其他文献

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{{ truncateString('Costantino Iadecola', 18)}}的其他基金

ApoE4, neurovascular injury and cognitive impairment
ApoE4、神经血管损伤和认知障碍
  • 批准号:
    10419353
  • 财政年份:
    2022
  • 资助金额:
    $ 59.9万
  • 项目类别:
High-speed imaging of cortical and white matter microvascular flow in AD/ADRD models
AD/ADRD 模型中皮质和白质微血管血流的高速成像
  • 批准号:
    10523289
  • 财政年份:
    2022
  • 资助金额:
    $ 59.9万
  • 项目类别:
ApoE4, Neurovascular Injury and Cognitive Impairment
ApoE4、神经血管损伤和认知障碍
  • 批准号:
    10593979
  • 财政年份:
    2022
  • 资助金额:
    $ 59.9万
  • 项目类别:
Alzheimer's Disease Viewed as a Neurovascular Inflammatory Disorder
阿尔茨海默病被视为一种神经血管炎症性疾病
  • 批准号:
    9195011
  • 财政年份:
    2016
  • 资助金额:
    $ 59.9万
  • 项目类别:
ApoE4 and mechanisms of diffuse white matter injury
ApoE4 与弥漫性白质损伤的机制
  • 批准号:
    9756482
  • 财政年份:
    2016
  • 资助金额:
    $ 59.9万
  • 项目类别:
ApoE4 and mechanisms of diffuse white matter injury
ApoE4 与弥漫性白质损伤的机制
  • 批准号:
    9355719
  • 财政年份:
    2016
  • 资助金额:
    $ 59.9万
  • 项目类别:
ApoE4 and mechanisms of diffuse white matter injury
ApoE4 与弥漫性白质损伤的机制
  • 批准号:
    9264693
  • 财政年份:
    2016
  • 资助金额:
    $ 59.9万
  • 项目类别:
Hypertension and neurovascular dysfunction
高血压和神经血管功能障碍
  • 批准号:
    8908643
  • 财政年份:
    2015
  • 资助金额:
    $ 59.9万
  • 项目类别:
Hypertension and neurovascular dysfunction
高血压和神经血管功能障碍
  • 批准号:
    9915965
  • 财政年份:
    2015
  • 资助金额:
    $ 59.9万
  • 项目类别:
Dietary Sodium, Neurovascular Dysfunction and Cerebrovascular Risk
膳食钠、神经血管功能障碍和脑血管风险
  • 批准号:
    10650322
  • 财政年份:
    2015
  • 资助金额:
    $ 59.9万
  • 项目类别:
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