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

摘要 空气污染是肌萎缩侧索硬化症(ALS)的一个未被充分研究的危险因素。ALS和空气污染导致- 燃烧，但没有研究将这两个关键的ALS主题联系起来。长期目标是预防、减缓或阻止 肌萎缩侧索硬化症的进展。总体目标是确定长期空气污染暴露如何改变ALS风险， 进展和生存，并深入了解炎症在神经元损伤过程中的作用。这个 中心假设是空气污染触发外周免疫模式，这是一种重要的病理生理机制。 肌萎缩侧索硬化症风险、进展和生存的逻辑代理。根据初步数据显示，i)ALS病例有 与对照组相比，颗粒物(PM)2.5暴露更高，II)PM2.5暴露最高的情况 已经增加了嗜酸性粒细胞、自然杀伤细胞标志物和细胞因子的激活，以及iii)现有的文献连接- 空气污染暴露于ALS疾病的严重性，其基本原理是将空气污染与ALS炎症性联系起来 个人资料将加强肌萎缩侧索硬化症和空气污染之间的联系，为关键和必要的预防措施提供信息 战略，以及定义新的疾病生物标记物和治疗目标。中心假设将是 通过追求两个具体目标进行测试：1)确定病例和控制措施中空气污染暴露的特征- Verity of Michigan ALS患者生物信息库，并确定这些暴露与ALS风险的关联，PRO 以及2)评估免疫状况作为空气污染和空气污染之间的联系的中介。 暴露与肌萎缩侧索硬化症的风险、进展和存活率之间的关系 密歇根州肌萎缩侧索硬化症患者生物信息库。在目标1a中，估算了病例和对照的空气污染暴露量。 使用完善的环境空气污染物预测模型，包括PM2.5、NO2和与交通相关的 空气污染物(陷阱)。暴露的时间跨度从2000年到2020年，占住宅HIS- 所有受试者的历史和ALS病例的症状出现日期。目标1b将调查这些暴露是如何- Cate与ALS风险，在Aim 1c中，与ALS进展和生存有关。AIM 2a将决定免疫亲和力- 与长期、时空、空气污染暴露相关的文件在目标1中开发。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，将在- 通过执行中介分析来研究免疫特征是否在因果途径中发挥作用- 空气污染与肌萎缩侧索硬化症的风险、进展和存活率之间的关系。本申请中提出的研究是创新的-- 申请人认为，这是因为它严格地开发了彻底的时空空气污染数据 捕捉时间和空间的空气污染趋势，并分析表型较深的肌萎缩侧索硬化症和对照队列 来自工业发达的中西部。这项拟议的研究具有重要意义，因为它将提供有关分布的关键数据。 与肌萎缩侧索硬化症的风险、进展和免疫途径相关的空气污染类型、免疫概况和免疫途径 生死存亡。归根结底，由于空气污染是一个可改变的风险因素，来自这项提议的知识可以指导Preven- 用于临床研究的治疗努力、治疗靶点和基于血液的生物标记物。

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.