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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：
Nabil J Alkayed
金额：
$ 165.9万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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：
https://reporter.nih.gov/project-details/10753185
关键词：
Age Age Months Aging Anti-Inflammatory Agents Autopsy B-Lymphocytes Biological Availability Blood - brain barrier anatomy Blood Preservation Blood Vessels Blood brain barrier dysfunction Brain Cells Cerebrovascular Circulation Cholesterol Chronic Clinical Cognitive Cognitive deficits Dementia Dependence Development Diabetes Mellitus Dyslipidemias Elderly Emotional Encephalitis Endothelial Cells Endothelium Epidemiology Epoxide hydrolase Exhibits Family Female Financial Hardship Flow Cytometry Healthcare Systems High Fat Diet Histopathology Human Hyperlipidemia Hypertension Immune Immunohistochemistry Impaired cognition Infiltration Inflammatory Invaded Leucocytic infiltrate Leukocytes Life Link Lipids LoxP-flanked allele Magnetic Resonance Imaging Maps Measurement Metabolic Metabolic Diseases Metabolic syndrome Microvascular Dysfunction Modeling Mus Neurocognitive Deficit Neutrophil Infiltration Obesity Patients Peripheral Process Property Public Health Recording of previous events Reporter Risk Risk Factors Role Severities Sex Differences Signaling Molecule Testing Therapeutic Time Up-Regulation Vascular Cognitive Impairment Vascular Endothelium Ventricular Wild Type Mouse age related aged blood-brain barrier crossing blood-brain barrier disruption blood-brain barrier permeabilization brain parenchyma brain tissue cardiovascular risk factor cerebral atrophy cerebrovascular cognitive testing enzyme activity glial activation human old age (65+)immune cell infiltrate inhibitor innovation male middle age morris water maze neuroinflammation novel object recognition overexpression pharmacologic prevent response secondary outcome single-cell RNA sequencing translational study treatment effect white 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.

摘要与衰老相关的痴呆症是一个主要的公共卫生问题，对病人、其家庭和保健系统造成经济压力。临床和流行病学证据表明存在血管和代谢危险因素，如肥胖、糖尿病、血脂异常和高血压，统称为代谢综合征（MetS），在中年增加的风险，老年痴呆症的严重程度。拟议的研究将使用MetS的慢性高脂饮食（HFD）模型，目的：探讨代谢综合征相关认知功能障碍（MetS-related cognitive dysfunction，MetSCD）的发病机制及年龄依赖性。我们在有痴呆症病史的人死后大脑和喂食HFD的小鼠大脑中进行了观察表明MetS增加脑中可溶性环氧化物水解酶（sEH）的表达和活性微血管内皮，导致其底物环氧二十碳三烯酸酯（ESTs）的生物利用度降低，具有抗炎作用。降低的内皮细胞活化倾向于内皮细胞活化，外周免疫细胞向脑实质的浸润、神经炎症和认知功能障碍。在支持sEH上调、神经炎症和认知障碍之间的因果关系，人sEH的内皮过表达表现出年龄依赖性神经炎症和认知缺陷， sEH的药理学抑制可防止HFD诱导的神经炎症和认知损害。我们将检验代谢综合征通过以下途径导致老年认知功能障碍的假设：外周免疫细胞和进行性神经炎症。Aim 1将使用雄性和雌性野生型（WT）小鼠和内皮特异性缺失sEH的小鼠，接受标准（STD）或高脂饮食（HFD），以确定内皮sEH在12和24月龄时MetSCD中的作用。Aim 2将使用流式细胞术，免疫组织化学（IHC）和单细胞RNAseq（scRNAseq），以确定HFD是否诱导年龄- 依赖性神经炎性反应，特征为中性粒细胞的早期浸润和延迟浸润 T和B淋巴细胞。我们将使用免疫细胞报告小鼠（Fgd 5-CreERT 2; Ai 9）来确认外周血淋巴细胞的表达。白细胞的起源，表征免疫细胞侵袭的时间过程，并确定内皮特异性 sEH的缺失防止免疫细胞浸润到HFD小鼠的脑中。目标3将确定sEH 抑制剂t-AUCB（脑渗透剂）和 GSK 2256294（不穿过血脑屏障，BBB）保护对抗慢性HFD小鼠的神经认知障碍。我们还将确定是否存在性别差异治疗效果。拟议的研究是高度翻译，并将促进了解机制和年龄依赖性MetSCD。年龄依赖性免疫细胞浸润的内皮起源 MetSC是新颖的，使用scRNAseq和使用Fgd 5-CreERT 2; Ai 9小鼠的免疫细胞命运作图也是新颖的。