Urban air pollution and cerebral hypoperfusion: aging and sex influences

城市空气污染和脑灌注不足：衰老和性别的影响

基本信息

批准号：
10216929
负责人：
William J Mack
金额：
$ 30.99万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10216929
关键词：
Aerosols Affect Age Aging Air Pollution Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid beta-Protein Atrophic Biological Markers Blood Vessels Blood capillaries C57BL/6 Mouse Cerebrovascular Disorders Chronic Clinical Research Cognitive aging Cognitive deficits Complement component C5 Corpus Callosum Data Dependence Deposition Diffuse Elderly Estradiol Exhibits Experimental Models Exposure to Failure Feedback Female Functional disorder Gene set enrichment analysis Genetic Heterogeneity Hippocampus (Brain)Impaired cognition Individual Inflammation Inflammation Mediators Inflammatory Injury Intervention Ischemia Joints Knockout Mice Knowledge Lectin Magnetic Resonance Imaging Memory impairment Metabolism Microglia Modeling Molecular Mus Mutation Nerve Degeneration Neurocognition Neurocognitive Deficit Neuronal Dysfunction Neuronal Injury Neurons Outcome Outcome Assessment Particulate Matter Pathogenesis Pathology Pathway interactions Perforant Pathway Pericytes Persons Predisposition Prevalence Process Reperfusion Therapy Risk Risk Assessment Role Sampling Secondary to Severities Sex Differences Stains System TLR4 gene Testing Tissues Toxic effect Transgenic Organisms Up-Regulation Vascular Dementia Vulnerable Populations Wild Type Mouse blood-brain barrier permeabilization cerebral hypoperfusion cerebrovascular density design entorhinal cortex experimental study fine particles hemodynamics hypoperfusion inflammatory marker innovation ischemic injury macrophage male middle age mouse model multiphoton microscopy nanoparticulate nanosized nervous system disorder neuroinflammation neuron loss neurotoxic neurotoxicity older women overexpression particle programs response to injury sex synergism tractography traffic-related air pollution transcriptome sequencing vascular factor white matter white matter damage white matter injury

Aerosols Affect Age Aging Air Pollution Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid beta-Protein Atrophic Biological Markers Blood Vessels Blood capillaries C57BL/6 Mouse Cerebrovascular Disorders Chronic Clinical Research Cognitive aging Cognitive deficits Complement component C5 Corpus Callosum Data Dependence Deposition Diffuse Elderly Estradiol Exhibits Experimental Models Exposure to Failure Feedback Female Functional disorder Gene set enrichment analysis Genetic Heterogeneity Hippocampus (Brain)Impaired cognition Individual Inflammation Inflammation Mediators Inflammatory Injury Intervention Ischemia Joints Knockout Mice Knowledge Lectin Magnetic Resonance Imaging Memory impairment Metabolism Microglia Modeling Molecular Mus Mutation Nerve Degeneration Neurocognition Neurocognitive Deficit Neuronal Dysfunction Neuronal Injury Neurons Outcome Outcome Assessment Particulate Matter Pathogenesis Pathology Pathway interactions Perforant Pathway Pericytes Persons Predisposition Prevalence Process Reperfusion Therapy Risk Risk Assessment Role Sampling Secondary to Severities Sex Differences Stains System TLR4 gene Testing Tissues Toxic effect Transgenic Organisms Up-Regulation Vascular Dementia Vulnerable Populations Wild Type Mouse blood-brain barrier permeabilization cerebral hypoperfusion cerebrovascular density design entorhinal cortex experimental study fine particles hemodynamics hypoperfusion inflammatory marker innovation ischemic injury macrophage male middle age mouse model multiphoton microscopy nanoparticulate nanosized nervous system disorder neuroinflammation neuron loss neurotoxic neurotoxicity older women overexpression particle programs response to injury sex synergism tractography traffic-related air pollution transcriptome sequencing vascular factor white matter white matter damage white matter injury

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项目摘要

Joint Effects of Air Pollution and Cerebral Hypoperfusion: Age and Sex Influence Emerging evidence suggests a strong association between traffic-related air pollution (TRAP) and cognitive aging. Clinical and experimental studies demonstrate white matter toxicity and hippocampal neuronal atrophy in the setting of particulate matter (PM) exposure. Little is known, however, about the underlying pathophysiology and selective vulnerabilities. Evidence supports a critical role for cerebral vascular dysfunction in the onset and progression of Alzheimer's disease (AD), with cortical hypoperfusion implicated in the pathogenesis of neuronal dysfunction and cognitive deficits. Studies have demonstrated increased memory impairment, hippocampal neuronal loss, and altered Aβ metabolism in APPSwInd and APP overexpressing mice exposed to chronic cerebral hypoperfusion (CCH). Individuals with AD or cognitive impairment may demonstrate increased susceptibility to deleterious effects of TRAP exposure through vascular mechanisms. This program leverages experimental models focused exclusively on the cerebrovascular contributions to AD/ cognitive decline. We hypothesize that nanoparticulate matter (nPM) exposure and CCH exhibit synergistic effects on neurodegenerative pathways from the entorhinal cortex and hippocampus including the perforant pathway and diffuse white matter tracts. Age and sex variances are evident in AD prevalence, with older women most affected. These factors also impact cerebrovascular reserve, ischemic injury response, and BBB permeability. The proposed project seeks to determine age and sex influences on nPM and CCH exposure alone, and in combination, through the following specific aims: 1) Examine age dependence for the individual/ joint effects of nPM exposure and CCH on white matter toxicity, hippocampal / entorhinal cortex neuronal injury, and neurocognition, 2) Examine sex differences in the independent/ joint effects of nPM and CCH on the above outcomes and, 3) Examine mechanistic pathways by which nPM promotes neurodegenerative processes in the setting of CCH. The nPM exposure model has been used in our group's prior studies. Near roadside urban nPM is collected by means of innovative particle samplers developed by the USC Aerosol group (Sioutas). Whole body exposures are administered. The CCH model has been refined and leveraged to examine inflammatory mediators and BBB. A factorial design will assess independent and combined effects of nPM and CCH on white matter toxicity, hippocampal/ entorhinal cortex injury, and neurocognition. When administered together, we expect these exposures to exhibit synergy. Consistent with AD pathologies, we expect older female mice to demonstrate greatest vulnerability. We hypothesize that effects are associated with inflammatory upregulation and BBB permeability. Baseline interactions established in wild type mice and data from Project 3 will be leveraged to study mechanism in EFAD-Transgenic and inducible macrophage/ microglial specific TLR4 knockout mice. Expected knowledge will advance our understanding of age and sex impact on neurotoxicity secondary to air pollution and vascular mechanisms of cognitive decline evident in AD.

空气污染和脑灌注灌注的关节作用：年龄和性别影响新兴证据表明，与交通相关的空气污染（陷阱）与认知之间有着密切的关联老化。临床和实验研究表明白质毒性和海马神经元萎缩在特定物质（PM）暴露的情况下。然而，关于基础知之甚少病理生理学和选择性脆弱性。证据支持脑血管功能障碍的关键作用在阿尔茨海默氏病（AD）的发作和进展中，皮质灌注不足与神经元功能障碍和认知缺陷的发病机理。研究表明记忆力增加损伤，海马神经元丧失以及Appswind和App过表达的Aβ代谢改变暴露于慢性脑灌注灌注（CCH）的小鼠。患有广告或认知障碍的人可能证明通过血管机制对陷阱暴露的有害影响的敏感性增加。该程序利用实验模型仅关注对AD/的脑血管贡献认知能力下降。我们假设纳米含量物质（NPM）暴露和CCH暴露协同作用对来自内嗅皮层和海马的神经退行性途径的影响，包括穿孔途径和弥漫性白质。年龄和性别差异是广告患病率的证据，年龄较大女性受影响最大。这些因素还影响脑血管储备，缺血性损伤反应和BBB 渗透性。拟议的项目旨在确定对NPM和CCH暴露的年龄和性别影响通过以下特定目的单独和结合结合：1）检查个人的年龄依赖性/ NPM暴露和CCH对白质毒性，海马 /内嗅皮层神经元的关节作用损伤和神经认知，2）检查NPM和CCH对独立/关节影响的性别差异高于结果和3）检查NPM促进神经退行性的机械途径 CCH设置的过程。 NPM暴露模型已在我们小组的先前研究中使用。靠近路边城市NPM是通过USC气雾剂开发的创新粒子样品收集的组（Sioutas）。全身接触。 CCH模型已被完善并利用检查炎症介质和BBB。阶乘设计将评估独立和联合效果 NPM和CCH关于白质毒性，海马/内嗅皮层损伤和神经认知。什么时候我们共同管理，我们希望这些暴露能够发现协同作用。与广告病理一致，我们期望年长的雌性小鼠表现出最大的脆弱性。我们假设效果是相关的炎症上调和BBB渗透性。在野生型小鼠和项目3的数据将被利用来研究EFAD转基因和诱导巨噬细胞/ 小胶质细胞特异性TLR4敲除小鼠。预期知识将提高我们对年龄和性别的理解对AD中的空气污染和血管机制继发的神经毒性的影响。