Extracellular vesicles in Environmental Epidemiology Studies of Aging

摘要 通过这个 RIVER 提案，我寻求支持来描述和理解早期的生物反应， 预测与年龄相关的疾病，这种疾病通常是由于生命早期发生的暴露而引起的。我的 主要关注点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。 研究表明，环境空气颗粒物污染会加速认知衰老长达 5 年。因为 痴呆症具有很强的年龄依赖性，仅仅推迟其发病就可能产生巨大的影响。对于 为了有效预防此类影响，我们需要开发不仅能反映不良暴露，还能反映不良暴露的生物标志物 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 在空气污染的影响完全显现之前检测到认知能力下降的开始的工具。 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一致的人体和体外 对细胞外囊泡（EV）启用的未被充分重视的细胞通信系统的研究。电动汽车 是纳米尺寸（0.05–1 μm）的膜结合囊泡，由人体细胞释放到血液中， 含有诸如 microRNA 之类的货物，可以整合到受体细胞中并改变其生物学特性。我们 已经建立了根据源细胞类型 (SCT) 使用表面标记分离循环 EV 的能力， EV源自释放它们的细胞。这些新方法将使我的实验室能够识别来自 受暴露影响的精确细胞类型和器官。我们将把这些新方法应用于大型队列 对现有血液样本和在多个时间点纵向收集的临床数据进行的研究 经过数十年的跟踪，以确定调解空气污染对人们的不利影响的具体沟通途径 大脑。根据初步证据和试点数据，我的假设是，由 肺部对空气污染的反应携带信号，包括 microRNA，这些信号可以到达大脑并 加速大脑老化。与此同时，我们将进行体外研究，调查肺部如何释放 EV 使用人类支气管上皮细胞培养和培养 3D 对空气污染的反应影响大脑功能 脑类器官——一种新模型，可用于研究年龄相关的神经退行性过程 相关的大脑健康恶化。此外，我将应用当前的数据科学技术来识别模式 由环境暴露激活并预测未来的健康结果。 我有信心能够成功领导这个项目。在过去的 10 年里，我在 16 个 NIH- 项目中担任 (M)PI 资助的奖项。我的作品已发表超过 450 种出版物，最近我被公认为是最优秀的人之一 引用了过去十年中最具影响力的研究人员。我展示了广阔的视野并做出了开创性的贡献 对理解分子机制的贡献，包括电动汽车，这是稳态的一部分 环境暴露引起的变化。灵活且持续的 RIVER 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巨大成功。

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.