Mapping the ALS Exposome to Gain New Insights into Disease Risk and Pathogenesis

绘制 ALS 暴露组图谱以获得对疾病风险和发病机制的新见解

基本信息

批准号：
10518348
负责人：
STUART A BATTERMAN
金额：
$ 13.26万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10518348
关键词：
ALS patients Accounting Address Affect Age Amyotrophic Lateral Sclerosis Autopsy Biological Biological Monitoring Body mass index Brain Complex Data Disease Disease Progression Environment Environmental Exposure Environmental Monitoring Environmental Pollutants Environmental Risk Factor Environmental and Occupational Exposure Exposure to Genes Genetic Genetic Predisposition to Disease Genetic Risk Geography Goals Heavy Metals Heterogeneity Hobbies Link Maps Measurement Measures Metabolic Michigan Modeling Nerve Degeneration Neuraxis Neurodegenerative Disorders Occupational Occupational Exposure Occupations Organophosphates Pathogenesis Patients Peripheral Pesticides Phenotype Physical activity Play Polychlorinated Biphenyls Population Predisposition Public Health Recording of previous events Reporting Risk Risk Factors Role Sampling Spinal Cord Surveys Testing Time Tissues Toxic Environmental Substances Toxin Trace metal Trauma Universities Work cohort demographics disorder prevention disorder risk epidemiologic data improved innovation insight interest modifiable risk new therapeutic target organochlorine pesticide organochlorine pesticide exposure outreach persistent organic pollutants pesticide exposure pleiotropism pollutant polybrominated diphenyl ether polygenic risk score public health intervention recruit repository sex translational impact uptake

项目摘要

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with complex unknown pathogenesis. Recent evidence supports a gene-time-environment hypothesis whereby environmental exposures trigger neurodegeneration when superimposed on a genetic risk profile. Supporting this premise, long-term adverse environmental exposures are linked to ALS risk and progression; we have shown that measured and reported pesticide exposures strongly increase ALS risk and that high levels of persistent organic pollutants (POPs) decrease ALS survival in ALS subjects in Michigan. Therefore, there is a need to delineate the “ALS exposome,” defined as the lifetime of environmental exposures that contributes to ALS risk. In this proposal, our objectives are to improve our ALS exposome model by enhancing insight into pollutant mixtures associated with ALS accounting for genetic risk, identifying periods of susceptibility to exposures, correlating toxin measurements in easily assessable biofluids with epidemiologic data, and identifying whether these environmental toxins are absorbed into the central nervous system (CNS) in order to improve insight into the gene-time-environment hypothesis in ALS. Our central hypothesis is that identifying environmental pollutants in biofluids and CNS tissues will advance models of ALS pathogenesis. In Aim 1, we will better characterize the ALS exposome by measuring environmental toxins in biological samples obtained longitudinally from ALS subjects from the University of Michigan ALS Patient Repository and age- and sex-matched controls across the State of Michigan to yield insight into the pollutant mixtures that contribute to disease risk and survival, accounting for genetic susceptibility via polygenic risk scores. In Aim 2, we will evaluate residential and occupational histories for association with ALS risk and survival, while also correlating exposure histories to toxin measures from Aim 1, to gain comprehensive insight into exposure mixtures and time windows critical for ALS risk. Finally, in Aim 3, we will quantitate environmental toxins and heavy metals in ALS and control CNS tissues, and link peripheral alterations with observed changes in ALS CNS tissue and critical exposure windows to thereby ascertain environmental risk factors that potentially contribute to ALS pathogenesis. Overall, successful completion of these aims will have an important positive translational impact by identifying ALS disease risk factors associated with occupational and environmental exposures, while accounting for genetic susceptibility. This proposal will therefore expand our understanding of the ALS exposome in the context of genetic risk, identify toxins that pose a public health risk, identify occupations linked to exposures, and establish a framework to test for these exposures in other neurodegenerative diseases. This understanding of the ALS exposome will support much-needed public health interventions to target modifiable disease risk factors in this lethal disorder.

抽象的肌萎缩侧索硬化症 (ALS) 是一种进行性、致命性的神经退行性疾病，其发病机制复杂且未知，最近的证据支持基因-时间环境假说，因此当环境暴露叠加在遗传风险特征上时，会引发神经退行性疾病，这支持了这一前提，即长期不利的环境。暴露与 ALS 风险和进展相关；我们已经表明，测量和报告的农药暴露会大大增加 ALS 风险，而高水平的持久性有机污染物 (POP) 会降低 ALS 受试者的 ALS 生存率。因此，有必要描述“ALS 暴露组”，定义为导致 ALS 风险的环境暴露寿命。在本提案中，我们的目标是通过增强对与 ALS 相关的污染物混合物的了解来改进我们的 ALS 暴露组模型。 ALS 考虑遗传风险，确定暴露的易感期，将易于评估的生物液体中的毒素测量值与流行病学数据相关联，并确定这些环境毒素是否被吸收到中枢神经系统中（CNS），以提高对 ALS 基因-时间-环境假说的认识。我们的中心假设是，识别生物体液和 CNS 组织中的环境污染物将推进 ALS 发病机制的模型。在目标 1 中，我们将更好地表征 ALS 暴露组。通过测量从密歇根大学 ALS 患者存储库的 ALS 受试者纵向获得的生物样本中的环境毒素以及整个密歇根州的年龄和性别匹配对照，以深入了解导致疾病风险和生存，通过多基因风险评分考虑遗传易感性在目标 2 中，我们将评估居住史和职业史与 ALS 风险和生存的关系，同时还将暴露史与目标 1 中的毒素测量相关联，以全面了解。对 ALS 至关重要的暴露混合物和时间窗口最后，在目标 3 中，我们将定量 ALS 中的环境毒素和重金属并控制 CNS 组织，并将外周变化与观察到的 ALS CNS 组织和关键暴露窗口的变化联系起来，从而确定可能导致 ALS 发病机制的环境风险因素。总体而言，通过识别与职业和环境暴露相关的 ALS 疾病风险因素，同时考虑遗传易感性，成功完成这些目标将产生重要的积极转化影响，因此，本提案将扩大我们对 ALS 疾病的理解。在遗传风险背景下进行 ALS 暴露，识别构成公共健康风险的毒素，识别与暴露相关的职业，并建立一个框架来测试其他神经退行性疾病中的这些暴露。对 ALS 暴露的了解将为急需的公众提供支持。针对可改变的疾病危险因素的健康干预措施致命的疾病。