Neural stem cell susceptibility to ambient particulate matter over the lifespan

描述(申请人提供)：环境空气污染物通过未知的机制对认知造成不利影响，并导致进行性神经变性。然而，众所周知，神经退行性疾病与神经发生的变化有关。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在环境空气污染中与儿童和成年人的认知缺陷联系在一起。儿童对环境污染物特别敏感，这种易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，而此时他们很容易受到环境污染物的影响。此外，环境空气污染加剧了成人阿尔茨海默病等神经退行性疾病的进展。在发育的关键时期和整个生命周期，暴露在环境空气污染物中会改变干细胞的功能和命运，从而导致神经元功能障碍。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，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。这项应用的目的是使用小鼠模型来测量暴露在真实世界空气污染中对神经干细胞的影响。中心假设是，无论处于什么发育阶段，周围空气中的污染物都会对神经发生产生不利影响。这项研究将利用一种独特的资源来获取真实世界的空气污染：五大湖空气综合环境研究中心(冰川)流动研究实验室，配备了整个动物吸入研究和大气监测。这将使整个动物接触到美国大湖区常见的多种污染物大气中特有的浓缩环境细颗粒物(PM2.5)。将在海马的颗粒下带(SGZ)和侧脑室的脑室下带(SVZ)检查神经发生。这些区域不仅持续地进行神经发生，而且还与认知和神经退行性疾病有关。其目的是确定(1)神经发生和(2)祖细胞命运易受空气污染物诱导的不利影响的发育阶段。这一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、积极的变化，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，因为它将为干细胞对可能改变的环境污染物的反应提供洞察力 干细胞的功能，干细胞的命运，或可能使个人容易患上疾病的细胞成分。

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.