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 通过这条河提案，我寻求支持，以表征和了解早期生物学反应 预期与年龄有关的疾病，通常是由于生活中早期发生的暴露而发展。我的 主要重点将是空气污染对我实验室的主要兴趣加速大脑衰老的影响。 环境空气颗粒污染已显示可将认知衰老加速多达5年。由于 痴呆症的强大年龄依赖性，仅延迟其发作可能会产生巨大的影响。为了 有效地防止这种影响，我们需要开发出反映不良暴露的生物标志物，还反映 对认知功能和大脑健康确定的临床前影响也是如此。也就是说，我们需要找到易于使用的 检测空气污染的影响和认知能力下降的开始之前的工具。 为了满足这种紧急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 对细胞外蔬菜（EVS）实现的细胞通信系统不足的研究。电动汽车 是纳米大小（0.05–1μM）人类细胞释放到血液中的膜结合的蔬菜 包含可以集成到受体细胞中并修改其生物学的货物，例如microRNA。我们 具有基于其源单元类型（SCT）的循环能力来建立能力 电动汽车源自释放它们的单元。这些新方法将使我的实验室能够从 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 现有的血液样本和临床数据的研究在多个时间点纵向收集 数十年的随访，以确定介导空气污染对不利影响的特定交流路线 大脑。根据初步证据和试点数据，我的假设是 响应于空气污染的肺携带信号，包括microRNA，可以到达大脑， 加速大脑衰老。同时，我们将进行体外研究，研究肺部释放的电动汽车如何 对空气污染的反应使用人支气管上皮细胞培养和培养的3D影响脑功能 脑器官 - 一种新型模型，可用于研究年龄的基础神经退行性过程 相关的大脑健康决定。此外，我将应用当前的数据科学技术来识别模式 环境暴露并预测未来健康结果。 我相信我可以成功地领导该计划。在过去的10年中，我在16个NIH-上担任（m）pi- 资助的奖项。我的作品制作了> 450个出版物，最近我被认为是最高的 引用了过去十年中最有影响力的研究人员。我已经表现出广泛的视野，并进行了开创性 对理解包括电动汽车在内的分子机制的理解的贡献，这些机制是体内平衡的一部分 环境暴露引起的改变。灵活且持续的河流支撑将有助于继续 非常成功的环境健康科学创新和领导能力的记录。