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（专注于专注的行政补充） 预计到2050年全球，痴呆症患者的估计人数为三倍。与缺乏 有效的治疗方法，以阻止，减慢或预防阿尔茨海默氏病（AD）及其相关痴呆症，最好 限制预测发生率的策略是减轻AD风险因素。暴露于环境颗粒物质 （PM）正在成为AD的可修改环境风险因素。但是，PM的机制 暴露有助于AD的发展。我们以前的研究表明暴露 到小鼠的超铁颗粒（UFP）和柴油排气（DE）导致慢性炎症，脂质增加 肺和全身组织的过氧化，脂质代谢和血浆脂蛋白的疾病以及 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成分 综合征。最近的研究表明，心血管和代谢性疾病可能在 广告的开发。实际上，AD和心脏代谢综合征具有主要风险因素 症状发生前几年发生的数年发生脑血管和心血管变化。基于其他 我们实验室的研究，UFP和DE暴露在小鼠中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的神经元并加速 认知能力下降。我们将通过扩展其专注于 肝脂肪变性和动脉粥样硬化，分析脑组织在同一高脂小鼠模型中 （低密度脂蛋白基因敲除，LDLR KO），放置在高脂肪饮食（HFD）上。重要的是，LDLR缺乏症和HFD 给药与AD的表型恶化有关 通过抗氧化剂系统防御导致氧化应激的抗氧化剂系统防御，AD的转基因小鼠模型 和神经元细胞凋亡。因此，尽管这不是用于AD研究的典型鼠标模型，但我们确实期望 明显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 肺心脑轴的途径可能参与了慢性炎症的发展 脑。我们对这种专注研究补充的假设是，PM暴露促进了 通过5-脂氧合酶途径的激活，促进和退化作用在大脑中 当激活持续进行时，要压倒稳态保护反应的抵消动作。 我们的假设将通过以下目的进行检验：补充特定目的1）确定分子 涉及神经炎症的发展和发展的途径以及与广告相关的变化 暴露于UFP后的大脑；和补充特异性目标2）剖析涉及的分子途径 暴露于DE后，神经炎症和与AD相关的大脑变化的发展和进展。 该补充剂的结果可以提供令人信服的初步数据，以进行其他建议以调查 可能导致AD和其他潜在驱动因素的认知能力下降的环境因素。