Dissecting the Role of Arachidonic Acid Metabolic Pathways Involved in Resolution Versus Progression of PM-Induced Cardiometabolic Toxicity

剖析花生四烯酸代谢途径在 PM 诱导的心脏代谢毒性的消退与进展中的作用

• 批准号: 10716093
• 负责人: Jesus Antonio Araujo
• 金额: $ 36.21万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716093
• 关键词: Acceleration; Administrative Supplement; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Antioxidants; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Astrocytes; Atherosclerosis; Brain; Cardiovascular Diseases; Cardiovascular system; Chronic; Critical Pathways; Data; Dementia; Development; Diesel Exhaust; Environmental Risk Factor; Exposure to; Fatty Liver; Heart; High Fat Diet; Impaired cognition; Impairment; Incidence; Inflammation; Inflammatory; Knock-out; Laboratories; Lead; Lipid Peroxidation; Lipoproteins; Low-Density Lipoproteins; Lung; Metabolic Diseases; Metabolic Pathway; Microglia; Molecular; Mus; Nerve Degeneration; Neurons; Oxidative Stress; Particulate Matter; Pathway interactions; Persons; Phenotype; Plasma; Play; Research; Resolution; Risk Factors; Role; Study models; Symptoms; Syndrome; System; Testing; Tissues; Toxic effect; Transgenic Mice; brain tissue; cardiometabolism; cerebrovascular; effective therapy; lipid metabolism; liver development; mouse model; neuroinflammation; neuron apoptosis; neurotoxicity; prevent; response; ultrafine particle

PROJECT SUMMARY/ABSTRACT (AD-focused Administrative Supplement) The estimated number of people with dementia is predicted to triple by 2050 worldwide. Together with the lack of effective treatments to stop, slow or prevent Alzheimer's disease (AD) and its related dementias, the best strategy to limit the predicted incidence is to mitigate AD risk factors. Exposure to ambient particulate matter (PM) is emerging as a modifiable environmental risk factor for AD. However, the mechanism by which PM exposure contributes to the development of AD is not known. Our previous research has shown that exposures to ultrafine particles (UFP) and diesel exhaust (DE) in mice lead to chronic inflammation, increased lipid peroxidation in lung and systemic tissues, disturbances in lipid metabolism and plasma lipoproteins, and the development of liver steatosis and atherosclerosis, all components of the commonly called cardiometabolic syndrome. Recent studies suggest that cardiovascular and metabolic disorders may play a critical role in the development of AD. In fact, AD and cardiometabolic syndrome share major risk factors, in addition to cerebrovascular and cardiovascular changes occurring years before symptoms occur. Based on additional research from our laboratories, both UFP and DE exposures in mice trigger astrocyte and microglia activation which lead to neuroinflammation and/or cause neurotoxicity affecting neurons in the brain and accelerating cognitive decline. We will augment the Parental R01 (ES033703, RESTORE RFA) by extending its focus on hepatic steatosis and atherosclerosis with the analyses of brain tissue in the same hyperlipidemic mouse model (low-density lipoprotein knockout, Ldlr KO), placed on a high fat diet (HFD). Importantly, Ldlr deficiency and HFD administration have been associated with worsened AD-related phenotypes and cognitive dysfunction in a transgenic mouse model of AD through impairment of antioxidant system defenses leading to oxidative stress and neuronal apoptosis. Therefore, while this is not a typical mouse model for the study of AD, we do expect significant neuroinflammatory and neurodegenerative effects. Our overall objective is to identify critical pathways in the Lung-Heart-Brain Axis that could be involved in the development of chronic inflammation in the brain. Our hypothesis for this AD-focused Research Supplement is that PM exposure promotes proinflammatory and degenerative effects in the brain via activation of the 5-Lipoxygenase pathway, overpowering the counteracting actions of homeostatic protective responses when that activation is persistent. Our hypothesis will be tested via the following aims: Supplemental Specific Aim 1) Determine molecular pathways involved in the development and progression of neuroinflammation and AD-relevant changes in the brain after exposure to UFP; and Supplemental Specific Aim 2) Dissect molecular pathways involved in the development and progression of neuroinflammation and AD-relevant changes in the brain after exposure to DE. Results from this Supplement could provide convincing preliminary data for additional proposals to investigate environmental factors that may induce AD and other potential drivers of cognitive decline.

项目摘要/摘要（以 AD 为重点的行政补充） 预计到 2050 年，全球痴呆症患者人数将增加两倍。与缺乏一起 阻止、减缓或预防阿尔茨海默病 (AD) 及其相关痴呆症的有效治疗方法，最好的方法 限制预测发病率的策略是减轻 AD 风险因素。暴露于环境颗粒物 (PM) 正在成为 AD 的一个可改变的环境风险因素。然而，PM 的机制 暴露是否会导致 AD 的发展尚不清楚。我们之前的研究表明，暴露 超细颗粒物 (UFP) 和柴油机尾气 (DE) 会导致小鼠慢性炎症、血脂增加 肺和全身组织的过氧化、脂质代谢和血浆脂蛋白的紊乱以及 肝脏脂肪变性和动脉粥样硬化的发展，通常称为心脏代谢的所有组成部分 综合症。最近的研究表明，心血管和代谢紊乱可能在 AD的发展。事实上，AD 和心脏代谢综合征有共同的主要危险因素，除了 脑血管和心血管变化发生在症状出现前数年。基于附加 我们实验室的研究表明，小鼠的 UFP 和 DE 暴露都会触发星形胶质细胞和小胶质细胞激活 导致神经炎症和/或引起神经毒性，影响大脑中的神经元并加速 认知能力下降。我们将通过扩展其重点来增强 Parental R01（ES033703、RESTORE RFA） 同一高脂小鼠模型中肝脂肪变性和动脉粥样硬化的脑组织分析 （低密度脂蛋白敲除，Ldlr KO），采用高脂肪饮食（HFD）。重要的是，Ldlr 缺乏和 HFD 给药与 AD 相关表型恶化和认知功能障碍有关 AD转基因小鼠模型通过抗氧化系统防御受损导致氧化应激 和神经元凋亡。因此，虽然这不是 AD 研究的典型小鼠模型，但我们确实期望 显着的神经炎症和神经退行性作用。我们的总体目标是确定关键 肺-心-脑轴中的通路可能参与慢性炎症的发展 脑。我们对这份以 AD 为重点的研究补充的假设是，PM 暴露会促进 通过激活 5-脂氧合酶途径对大脑产生促炎和退行性作用， 当这种激活持续存在时，会压倒稳态保护反应的抵消作用。 我们的假设将通过以下目标进行检验： 补充具体目标 1) 确定分子 参与神经炎症的发生和进展以及 AD 相关变化的途径 暴露于 UFP 后的大脑；和补充具体目标 2) 剖析参与的分子途径 暴露于 DE 后大脑中神经炎症和 AD 相关变化的发生和进展。 本补充文件的结果可以为其他调查提案提供令人信服的初步数据 可能诱发 AD 的环境因素和认知能力下降的其他潜在驱动因素。