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
- 来源:
- 关键词:AdhesionsAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAutomobile DrivingBacteriaBlood CirculationBlood PressureBlood capillariesBrainCardiovascular DiseasesCellsCerebrovascular CirculationCerebrumCognitionCognitiveCognitive deficitsConsumptionDataDementiaDietDietary FactorsDietary SodiumDown-RegulationEndothelial CellsEndotheliumEventExcess Dietary SaltFemaleFlow CytometryFoodFunctional disorderFundingGoalsHealthHelper-Inducer T-LymphocyteIL17 geneImmuneImmunologicsImpaired cognitionImpairmentIndividualLactobacillusLeadLeukocytesLifeLightLinkMediatingMediator of activation proteinMicrotubule-Associated ProteinsMicrovascular DysfunctionModelingMolecularMorbidity - disease rateMusNOS3 geneNeuronsNitric OxideNitric Oxide SynthasePerfusionPhasePhosphorylationProductionPublic HealthReceptor ActivationReporterResearchRestRiskRisk FactorsRoleScaffolding ProteinScienceSmall IntestinesSodium ChlorideSourceTauopathiesTestingTimeTranslatingadaptive immune responseagedbasebrain endothelial cellbrain healthcardiovascular risk factorcerebrovascularcytokinedietary excessdietary saltendothelial dysfunctionexperimental studygenetic regulatory proteinhigh salt diethyperphosphorylated tauhypoperfusionimprovedin vivoinsightlink proteinmalemicrobiotamortalityneurovascularnovelnovel strategiesprogramsreceptorreceptor downregulationreconstitutionresponsesalt intakesalt sensitivetau Proteinstau aggregationtranscriptome sequencingtwo photon microscopy
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.
全世界的盐消费量大大超过了最低要求,
盐已成为认知障碍和痴呆症的一个重要危险因素。增加
有证据表明,高盐饮食(HSD)对大脑健康有害,
盐敏感个体中与HSD相关的血压升高。不幸的是,公共
控制盐摄入量的健康努力是徒劳的,饮食中的盐消费量继续上升
国际吧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。
在上一个资助期,我们已经证明了小鼠的HSD导致大脑中
通过抑制内皮型一氧化氮(NO)而引起的脑血流(CBF)和认知障碍
生产这些作用是由小淋巴细胞中的辅助性T淋巴细胞亚类(Th 17)介导的。
肠,增加细胞因子IL 17的循环水平。IL 17反过来又导致抑制
内皮型一氧化氮合酶(eNOS)。导致的内皮细胞缺陷
NO通过过度磷酸化tau蛋白的神经元积累诱导认知障碍,
微管相关蛋白与阿尔茨海默病和相关痴呆症有关。然而,在这方面,
在肠道中触发IL 17产生的因素,IL 17受体的细胞定位
诱导eNOS抑制,CBF减少在tau积累中的作用仍有待进一步研究。
确立了习这一更新申请旨在促进对
HSD的认知效应通过测试以下新的假设:(a)HSD触发不同的先天性
和通过微生物群在肠道中的适应性免疫应答,(B)所导致的
循环IL 17作用于脑内皮IL 17受体,通过
eNOS调节蛋白纹状体蛋白的下调,和(c)白细胞粘附的增加
NO缺乏导致微血管闭塞(毛细血管停滞),
tau蛋白通过减少其进入血流的微血管清除而在脑中积累。我们将
在年轻和年老的雄性和雌性小鼠中使用HSD的良好表征模型,
本发明涉及检测肠-脑免疫相互作用,微血管功能,
过度磷酸化的tau蛋白和认知缺陷。这些研究促进了对
在细胞和分子水平上研究过量膳食盐的病理生物学,并可能导致新的
减少其对大脑健康的有害影响,导致认知障碍的方法。
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)
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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:
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: