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

项目摘要/摘要(侧重AD的行政副刊) 预计到2050年，全球痴呆症患者的估计数量将增加两倍。再加上缺乏 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 限制预测发病率的策略是减轻AD的危险因素。暴露在环境颗粒物中 (PM)正在成为AD的一个可改变的环境风险因素。然而，PM通过的机制 暴露对阿尔茨海默病的发展有何贡献尚不清楚。我们之前的研究表明，暴露在 超细颗粒物(UFP)和柴油尾气(DE)可导致小鼠慢性炎症、血脂升高 肺和全身组织中的过氧化反应，脂代谢和血浆脂蛋白的紊乱，以及 发生肝脏脂肪变性和动脉粥样硬化，所有成分俗称心脏代谢性疾病 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，阿尔茨海默病和心脏代谢综合征都是主要的危险因素，除了 脑血管和心血管的变化在症状出现前几年就发生了。基于其他 我们实验室的研究表明，UFP和DE暴露在小鼠体内都会引发星形胶质细胞和小胶质细胞的激活 会导致神经炎症和/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。我们将增强Parental R01(ES033703，恢复RFA)，将其重点扩展到 同一高脂血症模型小鼠肝脏脂肪变性和动脉粥样硬化及脑组织分析 (低密度脂蛋白基因敲除，Ldlr KO)，置于高脂饮食(HFD)中。重要的是，Ldlr缺乏和HFD 给药与AD相关表型和认知功能障碍的恶化有关 抗氧化系统防御功能受损导致氧化应激的转基因AD小鼠模型 和神经细胞的凋亡。因此，虽然这不是研究阿尔茨海默病的典型小鼠模型，但我们预计 显著的神经炎性和神经退行性改变。我们的总体目标是找出关键的 肺-心-脑轴中参与慢性炎症发展的途径 大脑。我们对这份以AD为重点的研究补充材料的假设是，PM暴露促进了 通过激活5-脂氧合酶途径在大脑中的促炎和退行性作用， 当这种激活持续时，压倒动态平衡保护性反应的抵消作用。 我们的假设将通过以下目的来检验：补充特定目的1)确定分子 神经炎症和AD相关改变的发生和发展途径 UFP暴露后的大脑；和补充特异性靶点2)剖析参与 DE暴露后脑神经炎症和AD相关改变的发生发展。 本附录的结果可以为进一步调查提供令人信服的初步数据 可能导致阿尔茨海默病的环境因素和其他可能导致认知能力下降的因素。

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.