Neural stem cell susceptibility to ambient particulate matter over the lifespan

描述（由申请人提供）：环境空气污染物对认知产生不利影响，并通过未知机制导致进行性神经退行性变。然而，已知神经退行性疾病与神经发生的变化相关。因此，环境空气污染物有可能改变神经发生和干细胞功能，从而导致神经元功能障碍。到目前为止，还没有调查研究环境空气污染物对神经发生的影响。新出现的数据将暴露于环境空气污染与儿童和成人的认知缺陷联系起来。儿童对环境污染物特别敏感，这种敏感性增加的机制尚未阐明。在儿童中，神经发生在发育中的大脑中以很高的速度发生，此时他们容易受到环境污染物的影响。此外，环境空气污染加剧了神经退行性疾病的进展，如成年人的阿尔茨海默病。在发育的关键时期和整个生命周期暴露于环境空气污染物可以改变干细胞的功能和命运，并在这样做时诱导神经元功能障碍。由于大约一半的美国人口（约1.54亿人）生活在空气质量有害的县，因此迫切需要了解环境空气污染物对神经发生和干细胞功能的根本影响。本申请的目的是使用小鼠模型测量暴露于现实世界的空气污染对神经干细胞的影响。中心假设是，环境空气污染物将不利地改变神经发生，无论发育阶段。这项研究将利用一个独特的资源，以获得现实世界的空气污染：五大湖空气综合环境研究中心（GLACIER）移动的研究实验室，配备了整个动物吸入研究和大气监测。这将使整个动物暴露于美国五大湖地区常见的多污染物大气中的特征浓缩环境细颗粒物（PM2.5）。将在海马的颗粒下区（SGZ）和侧脑室的脑室下区（SVZ）中检查神经发生。这些区域不仅持续进行神经发生，而且还与认知和神经退行性疾病有关。目的是确定发育阶段，其中（1）神经发生和（2）祖细胞命运易受空气污染引起的不利影响。这项拟议的探索性项目预计将揭示，主要空气污染物能够引起神经发生和干细胞功能的多种重要的不利变化，这些变化取决于暴露时的发育阶段。预期的结果将对人类健康产生积极影响，因为它将深入了解干细胞对环境污染物的反应， 干细胞功能、干细胞命运或可能使个体易患疾病的细胞组成。 超过50%的美国人口暴露在超过国家环境空气质量标准的空气质量中。颗粒空气污染与神经退行性疾病有关，其中神经发生可能会改变;然而，目前尚不清楚空气污染对神经发生的影响。拟议的研究与公共卫生有关，因为它将详细了解环境空气中颗粒物对从出生后到成熟成人的神经发生的影响，这是目前缺乏的。

DESCRIPTION (provided by applicant): Environmental air pollutants adversely affect cognition and cause progressive neurodegeneration through unknown mechanisms. It is known, however, that neurodegenerative disorders are associated with changes in neurogenesis. Thus, environmental air pollutants have the potential to alter neurogenesis and stem cell function, thereby causing neuronal dysfunction. To date, no investigation has examined the consequences of environmental air pollutants on neurogenesis. Emerging data link exposure to ambient air pollution and cognitive deficits in both children and adults. Children are especially sensitive to environmental pollutants and the mechanisms for this increased susceptibility have not been elucidated. In children neurogenesis takes place at a high rate in the developing brain, at a time when they are vulnerable to environmental pollutants. In addition, environmental air pollution exacerbates the progression of neurodegenerative disorders such as Alzheimer's disease in adults. Exposure to environmental air pollutants during critical periods of development and across lifespan can alter stem cell function and fate and, in so doing, induce neuronal dysfunction. As about half of the US populations (~ 154 million people) live in counties that have harmful air quality, there is an urgent need to understand the fundamental effects of environmental air pollutants on neurogenesis and stem cell function. The objective of this application is to measure the effects of exposure to real-world air pollution on neuronal stem cells using the mouse model. The central hypothesis is that ambient airborne pollutants will adversely alter neurogenesis regardless of the developmental stage. This research will utilize a unique resource to obtain real-world air pollution: the Great Lakes Air Center for Integrative Environmental Research (GLACIER) mobile research laboratory equipped for whole animal inhalation studies and atmospheric monitoring. This will allow whole animal exposure to characterized concentrated ambient fine particulate matter (PM2.5) from a multi-pollutant atmosphere commonly found in the Great Lakes Region of the United States. Neurogenesis will be examined in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. Not only do these regions continuously undergo neurogenesis, but they are also associated with cognition and neurodegenerative disorders. The aim is to identify developmental stages in which (1) neurogenesis and (2) progenitor cell fate are susceptible to air pollutant-induced adverse effects. This proposed exploratory project is expected to reveal that primary air pollutants are capable of eliciting multiple, important, advers changes in neurogenesis and stem cell function that are dependent on the developmental stage at the time of exposure. The expected outcome will have a positive impact on human health as it will provide insights into the response of stem cells to environmental pollutants that may alter stem cell function, stem cell fate, or the cellular composition that could predispose individuals towards disease. PUBLIC HEALTH RELEVANCE: Over 50% of the US population is exposed to air quality that exceeds National Ambient Air Quality Standards. Particulate air pollution has been linked to neurodegenerative disorders in which neurogenesis may be altered; however, it is not known what the effects of air pollution are on neurogenesis. The proposed research is relevant to public health because it will provide a detailed understanding of the effects of ambient airborne particulate matter on neurogenesis from the postnatal to the mature adult that is currently lacking.