Extracellular vesicles in Environmental Epidemiology Studies of Aging

总结 通过这项RIVER提案，我寻求支持来描述和理解早期生物反应， 预测与年龄有关的疾病，这通常是由于在生命早期发生的接触而引起的。我 主要的焦点将是空气污染对大脑加速老化的影响，这是我实验室的主要兴趣。 环境空气颗粒物污染已被证明会加速认知老化多达5年。因为 痴呆症的强烈年龄依赖性，仅仅延迟其发作就可能产生巨大的影响。为 为了有效地预防这些影响，我们需要开发生物标志物，不仅能反映不利的暴露， 还对认知功能和大脑健康恶化产生临床前影响。也就是说，我们需要找到易于使用的 这些工具可以检测空气污染的影响以及认知能力下降的开始，然后再完全显现出来。 为了解决这一紧迫的临床和公共卫生需求，我提出了一系列协调的人类和体外 研究了一个被低估的细胞通信系统，该系统由细胞外囊泡（EV）实现。EVs 是由人体细胞释放到血液中的纳米尺寸（0.05-1 μm）膜结合囊泡， 含有货物，如microRNA，可以整合到受体细胞和修改它们的生物学。我们 已经建立了基于其源细胞类型（SCT）使用表面标记分离循环EV的能力， EV来源于释放它们的细胞。这些新方法将使我的实验室能够识别来自 受辐射影响的细胞类型和器官我们将把这些新方法应用于大样本队列研究 在多个时间点纵向收集现有血液样本和临床数据的研究 几十年的后续行动，以确定具体的沟通途径，调解空气污染的不利影响， 大脑根据初步证据和试点数据，我的假设是， 肺对空气污染的反应携带信号，包括微RNA，可以到达大脑， 加速大脑衰老与此同时，我们将进行体外研究，调查肺释放的EV如何在 使用人支气管上皮细胞培养物和培养的3D对空气污染影响脑功能的反应 脑类器官-一种可用于研究年龄相关神经退行性过程的新模型- 与脑健康恶化有关。此外，我将应用当前的数据科学技术来识别模式 通过环境暴露激活并预测未来的健康结果。 我相信我能成功地领导这个项目。在过去的10年里，我担任（M）PI 16 NIH- 资助的奖项。我的作品已出版超过450种出版物，最近被评为最高出版物之一 过去十年中最有影响力的研究人员。我展示了广阔的视野， 有助于理解分子机制，包括EV，这是稳态的一部分， 由环境暴露引起的变化。灵活和持续的河流支持将有助于继续 在环境健康科学领域的创新和领导力方面取得了非常成功的记录。

SUMMARY Through this RIVER proposal, I seek support to characterize and understand early biological responses that anticipate age-related disease, which typically develops from exposures that occurred much earlier in life. My primary focus will be on the effects of air pollution on accelerated brain aging, a major interest of my lab. Ambient air particulate pollution has been shown to hasten cognitive aging by as much as 5 years. Because of the strong age dependence of dementia, merely delaying its onset could have a dramatic impact. For effectively preventing such effects, we need to develop biomarkers that reflect not only adverse exposures, but also preclinical effects on cognitive function and brain health deterioration. That is, we need to find easy-to-use tools to detect the impact of air pollution and the beginnings of cognitive decline before they manifest fully. To address this urgent clinical and public health need, I propose a series of coordinated human and in vitro studies of an underappreciated cellular communication system enabled by extracellular vesicles (EVs). EVs are nano-sized (0.05–1 μm) membrane-bound vesicles released by human cells into the bloodstream that contain cargo, such as microRNAs, that can be integrated into recipient cells and modify their biology. We have built capacity to isolate circulating EVs based on their source cell type (SCT) using surface markers that EVs derive from the cells that released them. These new methods will enable my lab to identify signals from the precise cell types and organs affected by the exposures. We will apply these new methods to large cohort studies with existing blood samples and clinical data collected longitudinally at multiple time points over decades of follow-up to identify specific communication routes mediating the adverse effects of air pollution on the brain. Based on preliminary evidence and pilot data, my hypothesis is that circulating EVs released by the lung in response to air pollution carry signals, including microRNAs, that can that reach the brain and accelerate brain aging. In parallel, we will conduct in vitro studies investigating how EVs released by the lung in response to air pollution affect brain function using human bronchial epithelial cell cultures and cultured 3D brain organoids—a novel model that can be used to study the neurodegenerative processes underlying age- related brain health deterioration. Further, I will apply current data science techniques to identify patterns activated by environmental exposures and predictive of future health outcomes. I am confident that I can successfully lead this program. Over the last 10 years, I served as (M)PI on 16 NIH- funded awards. My work has produced >450 publications, and I was recently recognized as one of the highest cited, most influential investigators of the past decade. I have demonstrated a broad vision and made seminal contributions to the understanding of molecular mechanisms, including EVs, that are part of homeostatic alterations caused by environmental exposures. The flexible and sustained RIVER support will help continue a highly successful record of innovation and leadership in environmental health sciences.