Neuroinflammatory Mechanisms of Vascular Cognitive Impairment
血管性认知障碍的神经炎症机制
基本信息
- 批准号:10753185
- 负责人:
- 金额:$ 165.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-15 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AgeAge MonthsAgingAnti-Inflammatory AgentsAutopsyB-LymphocytesBiological AvailabilityBlood - brain barrier anatomyBlood PreservationBlood VesselsBlood brain barrier dysfunctionBrainCellsCerebrovascular CirculationCholesterolChronicClinicalCognitiveCognitive deficitsDementiaDependenceDevelopmentDiabetes MellitusDyslipidemiasElderlyEmotionalEncephalitisEndothelial CellsEndotheliumEpidemiologyEpoxide hydrolaseExhibitsFamilyFemaleFinancial HardshipFlow CytometryHealthcare SystemsHigh Fat DietHistopathologyHumanHyperlipidemiaHypertensionImmuneImmunohistochemistryImpaired cognitionInfiltrationInflammatoryInvadedLeucocytic infiltrateLeukocytesLifeLinkLipidsLoxP-flanked alleleMagnetic Resonance ImagingMapsMeasurementMetabolicMetabolic DiseasesMetabolic syndromeMicrovascular DysfunctionModelingMusNeurocognitive DeficitNeutrophil InfiltrationObesityPatientsPeripheralProcessPropertyPublic HealthRecording of previous eventsReporterRiskRisk FactorsRoleSeveritiesSex DifferencesSignaling MoleculeTestingTherapeuticTimeUp-RegulationVascular Cognitive ImpairmentVascular EndotheliumVentricularWild Type Mouseage relatedagedblood-brain barrier crossingblood-brain barrier disruptionblood-brain barrier permeabilizationbrain parenchymabrain tissuecardiovascular risk factorcerebral atrophycerebrovascularcognitive testingenzyme activityglial activationhuman old age (65+)immune cell infiltrateinhibitorinnovationmalemiddle agemorris water mazeneuroinflammationnovelobject recognitionoverexpressionpharmacologicpreventresponsesecondary outcomesingle-cell RNA sequencingtranslational studytreatment effectwhite matter damage
项目摘要
ABSTRACT
Aging-related dementia is a major public health concern that places an enormous emotional, physical, and
financial stress on patients, their families and health-care systems. Clinical and epidemiological evidence
suggests that the presence of vascular and metabolic risk factors, such as obesity, diabetes, dyslipidemia and
hypertension, collectively known as the metabolic syndrome (MetS), during midlife increases the risk for and
severity of dementia in late-life. The proposed studies will use the chronic high-fat diet (HFD) model of MetS in
mice to investigate the mechanism and age-dependency of MetS-related cognitive dysfunction (MetSCD).
Our observations made in postmortem human brain with a history of dementia and in brains of HFD-fed mice
suggest that MetS increases the expression and activity of the enzyme soluble epoxide hydrolase (sEH) in brain
microvascular endothelium, leading to reduced bioavailability of its substrate epoxyeicosatrienoates (EETs),
which have anti-inflammatory properties. Reduced endothelial EETs predisposes to endothelial cell activation,
peripheral immune cell infiltration into brain parenchyma, neuroinflammation and cognitive dysfunction. In
support of a causal link between sEH upregulation, neuroinflammation and cognitive impairment, mice with
endothelial overexpression of human sEH exhibit age-dependent neuroinflammation and cognitive deficit, while
pharmacological inhibition of sEH protects against HFD-induced neuroinflammation and cognitive impairment.
We will test the hypothesis that MetS contributes to late-life cognitive dysfunction via the infiltration of
peripheral immune cells and progressive neuroinflammation. Aim 1 will use male and female wild-type (WT)
mice and mice with endothelial-specific deletion of sEH, on standard (STD) or high-fat diet (HFD), to determine
the role of endothelial sEH in MetSCD at 12 and 24 months of age. Aim 2 will use flow cytometry,
immunohistochemistry (IHC) and single-cell RNAseq (scRNAseq) to determine if HFD induces an age-
dependent neuroinflammatory response characterized by early infiltration of neutrophils and delayed infiltration
of T and B lymphocytes. We will use immune cell reporter mice (Fgd5-CreERT2;Ai9) to confirm the peripheral
origin of leukocytes, characterize the time course of immune cell invasion, and determine if endothelial-specific
deletion of sEH prevents immune cell infiltration into the brain of mice on HFD. Aim 3 will determine if sEH
inhibitors t-AUCB (brain-penetrant) and
GSK2256294 (does not cross the blood-brain barrier, BBB)
protect
against neurocognitive impairment in mice on chronic HFD. We will also determine if there are sex differences
in treatment effects. The proposed studies are highly translational, and will advance understanding of
mechanisms and age-dependency MetSCD. The endothelial origin of age-dependent immune cell infiltration in
MetSC is novel, and so is the use of scRNAseq and immune cell fate mapping using Fgd5-CreERT2; Ai9 mice.
摘要
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cytochrome P450-derived eicosanoids in brain: From basic discovery to clinical translation.
大脑中细胞色素 P450 衍生的类二十烷酸:从基础发现到临床转化。
- DOI:10.1016/bs.apha.2022.11.002
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Davis,CatherineM;Ibrahim,AseelH;Alkayed,NabilJ
- 通讯作者:Alkayed,NabilJ
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Nabil J Alkayed其他文献
Nabil J Alkayed的其他文献
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{{ truncateString('Nabil J Alkayed', 18)}}的其他基金
GPR39 as a Therapeutic Target in Aging-Related Vascular Cognitive Impairment and Dementia
GPR39 作为衰老相关血管认知障碍和痴呆的治疗靶点
- 批准号:
10734713 - 财政年份:2023
- 资助金额:
$ 165.9万 - 项目类别:
Training in Translational Science and Cardiovascular Research
转化科学和心血管研究培训
- 批准号:
10711526 - 财政年份:2023
- 资助金额:
$ 165.9万 - 项目类别:
Soluble Epoxide Hydrolase Inhibitor GSK2256294 for Acute Ischemic Stroke
可溶性环氧化物水解酶抑制剂 GSK2256294 用于治疗急性缺血性中风
- 批准号:
10672750 - 财政年份:2023
- 资助金额:
$ 165.9万 - 项目类别:
GPR39 as a Therapeutic Target in Subarachnoid Hemorrhage (SAH)
GPR39 作为蛛网膜下腔出血 (SAH) 的治疗靶点
- 批准号:
10478533 - 财政年份:2022
- 资助金额:
$ 165.9万 - 项目类别:
Role of GPR39 in Aging-Related Vascular Cognitive Impairment (VCI)
GPR39 在衰老相关血管认知障碍 (VCI) 中的作用
- 批准号:
10538329 - 财政年份:2022
- 资助金额:
$ 165.9万 - 项目类别:
Endothelial-Pericyte Crosstalk in Diabetic Stroke
糖尿病中风的内皮-周细胞串扰
- 批准号:
10400506 - 财政年份:2021
- 资助金额:
$ 165.9万 - 项目类别:
Pericyte phenotypic switching in diabetic post-stroke cognitive impairment (PSCI)
糖尿病中风后认知障碍(PSCI)中的周细胞表型转换
- 批准号:
10855709 - 财政年份:2018
- 资助金额:
$ 165.9万 - 项目类别:
Endothelial-Pericyte Crosstalk in Diabetic Stroke
糖尿病中风的内皮-周细胞串扰
- 批准号:
10338161 - 财政年份:2018
- 资助金额:
$ 165.9万 - 项目类别:
Neuroinflammatory mechanisms of aging-related vascular cognitive impairment (VCI)
衰老相关血管性认知障碍(VCI)的神经炎症机制
- 批准号:
9461247 - 财政年份:2017
- 资助金额:
$ 165.9万 - 项目类别:
DRα1-MOG: A Novel Immunomodulatory Therapeutic for Stroke
DRα1-MOG:一种新型中风免疫调节疗法
- 批准号:
9409245 - 财政年份:2017
- 资助金额:
$ 165.9万 - 项目类别:














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