Air Pollution and Central Nervous System Disease

描述(申请人提供)：这个少数民族职业发展奖的重点是建立空气污染物与脑神经发育和神经退行性疾病之间的关系。这将在一个高度支持的机构环境中实现，拥有多学科的专业知识、最先进的设备和设施，深深致力于成功的指导体验。该研究计划基于这样的假设，即空气污染物会产生呼吸道炎症，然后产生能够到达大脑(包括胎儿大脑)的炎症介质。此外，污染物从嗅觉上皮通过神经通路直接进入大脑。这项为期五年的研究计划分为三个阶段：第一阶段：城市污染对健康犬的脑和鼻、呼吸道和嗅觉组织的DNA氧化损伤。这一阶段的创新是研究自然暴露的动物，应用一系列高灵敏的分析方法来测量氧化DNA损伤作为生物标记物，以便确定持续氧化应激与神经退行性疾病之间的联系。通过选择直接自由基和脂质过氧化诱导的DNA损伤的生物标记物，将有可能确定污染暴露的大脑中氧化损伤的途径。这些结果将与神经病理学和免疫组织化学的改变进行比较和对比。阶段II。暴露在城市污染中的儿童和成人大脑中的DNA氧化损伤和炎症介质。这一阶段的主要目标是确定长期接触污染物引起的持续炎症过程是否会导致认知和神经功能完好的受试者脑部氧化DNA损伤和/或炎症介质的改变，以及是否存在神经病理对应的情况。阶段III.暴露在空气污染物中发育中的狗脑中的DNA损伤和炎症介质。这一阶段解决了这一提议的症结：污染对暴露的胎儿的影响。该奖项将让我有机会在四个领域建立新的技能：分子生物学、DNA损伤、发育/神经退行性神经病理学，并获得赠款方面的经验。

DESCRIPTION (provided by applicant): This Minority Career Development Award is focused on establishing the relationship between air pollutants and brain neurodevelopmental and neurodegenerative diseases. This will be accomplished in an institutional environment that is highly supportive, with multidisciplinary expertise, state-of-the art equipment and facilities that is deeply committed to a successful mentoring experience. The research plan is based on the hypothesis that air pollutants produce respiratory tract inflammation, followed by the production of mediators of inflammation capable of reaching the brain (including the fetal brain). In addition, pollutants directly enter the brain through neural pathways from the olfactory epithelium. The 5-year research plan is divided in 3 stages: Stage I. Oxidative DNA damage in brain and nasal respiratory and olfactory tissues of healthy canines exposed to urban pollution. The innovation of this stage is to study naturally exposed animals, apply a spectrum of highly sensitive assays to measure oxidative DNA damage as a biomarker so that the association between persistent oxidative stress and neurodegenerative diseases can be identified. By selecting biomarkers of direct radical and lipid peroxidation-induced DNA damage it will be possible to determine the pathways of oxidative damage in pollution-exposed brains. These results will be compared and contrasted with alterations in neuropathology and immunohistochemistry. Stage II. DNA oxidative damage and mediators of inflammation in brains of children and adults exposed to urban pollution. The main objective of this stage is to determine if a sustained inflammatory process elicited by chronic exposure to pollutants causes brain oxidative DNA damage and/or alterations in mediators of inflammation in cognitively and neurologically intact subjects residents in highly polluted cities, and if there is a neuropathology counterpart. Stage III. DNA damage and mediators of inflammation in the developing dog brain exposed to air pollutants. This stage addresses the crux of this proposal: Effects of pollution upon the exposed fetus. The Award will give me the opportunity to build new skills in 4 areas: Molecular Biology, DNA Damage, Developmental / Neurodegenerative Neuropathology, and to gain experience in grantsmanship.