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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：
10294245
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/10294245
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.

摘要