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：
10538554
负责人：
STUART A BATTERMAN
金额：
$ 65.31万
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/10538554
关键词：
ALS patients Accounting Affect Age Amyotrophic Lateral Sclerosis Autopsy Biological Biological Monitoring Body mass index Brain Central Nervous System 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 Neurodegenerative Disorders Occupational Occupational Exposure Occupations Organophosphates Pathogenesis Patients Peripheral Pesticides Phenotype Physical activity Polychlorinated Biphenyls Population Predisposition Public Health Recording of previous events Reporting Risk Risk Factors Sampling Spinal Cord Surveys Testing Time Tissues Toxic Environmental Substances Toxin Trace metal Trauma Universities Work absorption cohort comparison control 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

ALS patients Accounting Affect Age Amyotrophic Lateral Sclerosis Autopsy Biological Biological Monitoring Body mass index Brain Central Nervous System 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 Neurodegenerative Disorders Occupational Occupational Exposure Occupations Organophosphates Pathogenesis Patients Peripheral Pesticides Phenotype Physical activity Polychlorinated Biphenyls Population Predisposition Public Health Recording of previous events Reporting Risk Risk Factors Sampling Spinal Cord Surveys Testing Time Tissues Toxic Environmental Substances Toxin Trace metal Trauma Universities Work absorption cohort comparison control 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

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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.

抽象的肌萎缩性侧面硬化症（ALS）是一种进行性和致命的神经退行性疾病，具有复杂的发病机理。最近的证据支持了基因时间环境假说，在遗传风险概况上叠加时，环境暴露会触发神经退行性。支持这一前提，长期不利的环境暴露与ALS风险和发展有关；我们已经表明，测量和报告的农药暴露会大大增加ALS风险，高水平的有机污染物（POP）降低了密歇根州ALS受试者的ALS存活率。因此，有必要描绘“ ALS暴露”，这被定义为有助于ALS风险的环境暴露的寿命。 In this proposal, our objectives are to improve our ALS exposure 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 ALS中的基因时间 - 环境假设。我们的中心假设是，鉴定生物流体和中枢神经系统组织中的环境污染物将推动ALS发病机理的模型。在AIM 1中，我们将更好地表征通过测量来自密歇根大学ALS ALS患者存储库以及密歇根州的年龄和性别匹配对照的生物学样本中的环境毒素，从而洞悉疾病风险和属性疾病的污染物。在AIM 2中，我们将评估居民和占据与ALS风险和生存的关联的居民和占据历史，同时还将暴露历史与AIM 1的毒素测量相关联，从风险。最后，在AIM 3中，我们将定量ALS和控制中枢神经系统时机中的环境毒素和重金属，并将周围变化与观察到的ALS CNS组织的变化和关键的暴露窗口联系起来，从而确定环境风险因素，从而可能有助于ALS病原体。总体而言，通过确定与职业和环境暴露相关的ALS疾病风险因素，在考虑遗传敏感性的同时，成功完成这些目标将产生重要的积极翻译影响。因此，该提案将扩大我们对在遗传风险背景下暴露的ALS的理解，确定构成公共卫生风险的毒素，确定与暴露有关的职业，并建立一个在其他神经退行性疾病中测试这些暴露的框架。对暴露的ALS的这种理解将支持急需的公共卫生干预措施，以靶向可修改的疾病危险因素致命疾病。