Extracellular vesicles in Environmental Epidemiology Studies of Aging

细胞外囊泡在衰老环境流行病学研究中的应用

• 批准号: 10654005
• 负责人: Andrea Baccarelli
• 金额: $ 93.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-05 至 2029-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654005
• 关键词: Acceleration; Address; Adverse effects; Affect; Age; Aging; Air; Air Pollution; Award; Binding; Biological; Biological Markers; Biology; Blood; Blood Circulation; Blood specimen; Brain; Cell Culture Techniques; Cells; Chronic Disease; Clinical; Clinical Data; Cognitive aging; Cohort Studies; Communication; Data; Data Science; Dementia; Dependence; Deterioration; Disease; Early identification; Environmental Epidemiology; Environmental Exposure; Environmental Health; Functional disorder; Funding; Future; Health; Human; Human body; Impaired cognition; In Vitro; Influentials; Laboratories; Lead; Leadership; Life; Lung; Mediating; Membrane; Methods; MicroRNAs; Modeling; Molecular; Nerve Degeneration; Organ; Organoids; Outcome; Particulate; Pattern; Pollution; Process; Public Health; Publications; Research Personnel; Role; Route; Seminal; Series; Signal Transduction; Source; Surface; System; Techniques; Time; United States National Institutes of Health; Vision; Work; age related; aging brain; brain health; bronchial epithelium; cell type; cognitive function; epidemiology study; extracellular vesicles; flexibility; follow-up; innovation; interest; nanosized; novel; pre-clinical; prevent; programs; response; stem; three dimensional cell culture; tool; vesicular release

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.

概括 通过这个 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。 主要关注点是空气污染对加速大脑老化的影响，这是我实验室的主要兴趣。 环境空气颗粒污染已被证明会加速认知衰老长达 5 年。 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。 有效预防此类影响，我们需要开发不仅反映不良暴露，而且反映不良暴露的生物标志物 还有对认知功能和大脑健康恶化的临床前影响，也就是说，我们需要找到易于使用的方法。 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。 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。 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， 这些新方法将使我的实验室能够识别来自释放它们的细胞的信号。 我们将把这些新方法应用到大型队列中。 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 数十年的后续行动，以确定调解空气污染对人们的不利影响的具体沟通途径 根据初步证据和试点数据，我的假设是，循环电动汽车是由大脑释放的。 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 与此同时，我们将进行体外研究，研究肺部如何释放 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 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 10 年里，我担任 16 个 NIH 的 (M)PI。 我的作品已发表超过 450 种出版物，最近我被公认为最高的奖项之一。 我引用了过去十年中最有影响力的研究人员的观点，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 灵活且持续的 RIVER 支持将有助于继续保持环境暴露造成的变化。 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。