Linking long-term air pollution exposure with inflammation, ALS risk, and disease progression

将长期空气污染暴露与炎症、ALS 风险和疾病进展联系起来

• 批准号: 10488048
• 负责人: Eva Lucille Feldman
• 金额: $ 49.92万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488048
• 关键词: Linking; long; term; air; pollution

ABSTRACT Air pollution is an understudied amyotrophic lateral sclerosis (ALS) risk factor. ALS and air pollution cause in- flammation, yet no studies link these two critical ALS topics. The long-term goals are to prevent, slow, or stop ALS progression. The overall objective is to determine how long-term air pollution exposure alters ALS risk, progression, and survival and gain insight into the role of inflammation on the path to neuronal damage. The central hypothesis is that air pollution triggers peripheral immune profiles that are an important pathophysio- logic agent of ALS risk, progression and survival. Guided by preliminary data showing that i) ALS cases have higher particulate matter (PM)2.5 exposure compared to controls, ii) the cases with the highest PM2.5 exposures have increased eosinophils, natural kill cell markers, and cytokine activation, and iii) existing literature connect- ing air pollution exposure to ALS disease severity, the rationale is that linking air pollution to ALS inflammatory profiles will strengthen the association between ALS and air pollution to inform critical and needed preventative strategies, as well as define new disease biomarkers and therapeutic targets. The central hypothesis will be tested by pursuing two specific aims: 1) Characterize air pollution exposures for cases and controls in the Uni- versity of Michigan ALS patient biorepository and determine how these exposures associate with ALS risk, pro- gression, and survival; and 2) Evaluate immune profiles as a mediators of the associations between air pollu- tion exposures and ALS risk, progression, and survival using data from cases and controls in the University of Michigan ALS patient biorepository. In Aim 1a, air pollution exposures for cases and controls are estimated using well-established prediction models for key ambient air pollutants including PM2.5, NO2, and traffic related air pollutants (TRAPs). Exposures will span the years 2000 through 2020 and account for the residential his- tory for all subjects and symptom onset date for ALS cases. Aim 1b will investigate how these exposures asso- ciate with ALS risk and, in Aim 1c, with ALS progression and survival. Aim 2a will determine the immune pro- files that associate with long-term, spatiotemporal, air pollution exposures developed in Aim 1. As the literature links air pollution to inflammation and inflammation is linked to ALS progression and survival, Aim 2b, will in- vestigate whether immune profiles play a role in the causal pathway by performing a mediation analysis be- tween air pollution and ALS risk, progression, and survival. The research proposed in this application is innova- tive, in the applicants’ opinion, because it rigorously develops thorough spatiotemporal air pollution data that captures temporal and spatial air pollution trends and analyzes a deeply phenotyped ALS and control cohort from the industrial Midwest. The proposed research is significant because it will provide critical data on the dis- tinct types of air pollution, immune profiles, and immune pathways associated with ALS risk, progression, and survival. Ultimately, as air pollution is a modifiable risk factor, knowledge from this proposal can guide preven- tion efforts, therapeutic targets, and blood-based biomarkers for use in clinical studies.

抽象的 空气污染是一种理解的肌萎缩性侧面硬化症（ALS）危险因素。 ALS和空气污染导致 燃料，但没有研究将这两个关键ALS主题联系起来。长期目标是预防，减慢或停止 ALS进展。总体目的是确定长期空气污染的暴露如何改变ALS的风险， 进展，生存并洞悉炎症在神经元损伤的道路上的作用。 中心假设是空气污染触发了周围免疫特征，这是重要的病理学 ALS风险，进展和生存的逻辑代理。在初步数据的指导下，表明i）ALS案件具有 与对照组相比，较高的颗粒物物质（PM）2.5暴露，ii）PM2.5暴露最高的病例 嗜酸性粒细胞增加，自然杀死细胞标记和细胞因子激活，iii）现有文献连接 - 空气污染暴露于ALS疾病严重程度，理由是将空气污染与ALS炎症联系起来 概况将加强ALS与空气污染之间的关联，以告知关键和所需的预防措施 策略以及定义的新疾病生物标志物和治疗靶标。中心假设将是 通过追求两个具体目的测试：1）表征案件和控制的空气污染暴露 密歇根州ALS患者生物库的版本，并确定这些暴露与ALS风险相关的暴露方式 光泽和生存； 2）评估免疫谱作为空气粉之间关联的介体 使用来自案例和对照的数据的数据，暴露和ALS风险，进展和生存风险和生存 密歇根州ALS患者生物座席。在AIM 1A中，估计对病例和控制的空气污染暴露 使用公认的预测模型，用于关键环境空气污染物，包括PM2.5，NO2和与交通有关的预测模型 空气污染物（陷阱）。暴露将跨度为2000年至2020年，并说明居民的历史 所有受试者的保守党和ALS病例的症状发作日期。 AIM 1B将研究这些暴露方式如何 与ALS风险相提并论，在AIM 1C中，ALS的进展和生存。 AIM 2A将确定免疫支持 与AIM 1相关的长期，时空，空气污染暴露的文件。作为文献 将空气污染与炎症和炎症联系起来，与ALS的进展和生存有关，AIM 2B，将融入 对免疫特征是否在因果途径中发挥作用。 推特空气污染和ALS风险，进展和生存。本应用程序中提出的研究是创新的 在申请人的看来，Tive因为它严格地诚实地发展了时空空气污染数据 捕获临时和空间污染趋势，并分析深层的表型ALS和控制队列 来自中西部工业。拟议的研究很重要，因为它将提供有关疾病的关键数据 与ALS风险，进展和 生存。最终，由于空气污染是可修改的危险因素，因此从该提案中知道可以指导预防 - 用于临床研究的工作，治疗靶标和基于血液的生物标志物。