Impact of Geospatial Factors and Environmental Pollutants on Amyotrophic Lateral Sclerosis in the State of Michigan

地理空间因素和环境污染物对密歇根州肌萎缩侧索硬化症的影响

基本信息

批准号：
10163055
负责人：
Stephen Goutman
金额：
$ 20.21万
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：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163055
关键词：
ALS patients Address Affect Amyotrophic Lateral Sclerosis Blood Case-Control Studies Characteristics Clinic Clinical Collaborations Complex Cycad DNA Sequence Alteration Data Development Disease Disease Outcome Disease Progression Environment Environmental Exposure Environmental Impact Environmental Pollutants Environmental Pollution Environmental Risk Factor Epigenetic Process Excision Exposure to Functional disorder Future Genes Genetic Genetic Predisposition to Disease Genetic Risk Goals Hazardous Waste Sites Heterogeneity Incidence Individual Knowledge Measures Methods Michigan Modeling Motor Neurons Nerve Degeneration Neurodegenerative Disorders Newly Diagnosed Occupational Outcome Pathogenesis Patients Persons Phenotype Play Population Predisposition Prevalence Probability Proportional Hazards Models Public Health Questionnaires Recording of previous events Registries Regression Analysis Reporting Research Risk Risk Factors Role Site Testing Therapeutic Time Toxic Environmental Substances Universities Variant biobank biomarker discovery burden of illness disorder prevention disorder risk geographic difference improved innovation insight modifiable risk motor neuron degeneration persistent organic pollutants pleiotropism pollutant prevent translational impact

项目摘要

Project Summary/Abstract There is a fundamental gap in understanding how environmental exposures affect the development and clinical expression of amyotrophic lateral sclerosis (ALS). Continued existence of this gap represents an important problem, because until it is filled, understanding how specific environmental toxins affect the pathophysiology of ALS (1) hampers the ability to delineate ALS mechanisms and thereby limit treatment opportunities and (2) prevents the removal of modifiable risk factors from the environment. The long-term goals are to determine the influence of environmental toxins on the genetic susceptibility and pathogenesis of ALS, contextualize our data to support the National ALS registry, and promote therapeutic and biomarker discovery. The overall objective of this application is to identify persistent organic pollutants that associate with ALS disease expression. The central hypothesis is that persistent organic pollutants alter ALS incidence and disease factors such as surviv- al. The rationale for the proposed research is that discovering and delineating the impact of environmental tox- ins on ALS can identify a modifiable disease risk and also inform our understanding of the disease’s patho- physiology. Guided by strong preliminary data, this hypothesis will be tested by pursing two specific aims: 1) Determine how exposure to persistent organic pollutants modifies ALS disease expression in patients followed at the University of Michigan ALS Clinic; and 2) Expand the assessments of ALS and environmental exposures statewide to determine if geospatial clusters of ALS occur in Michigan and characterize their relationship to known sites of environmental pollution. Under the first aim the impact of environmental exposures--derived via a detailed questionnaire combined with measured persistent organic pollutant levels in blood--on region of on- set, survival, and disease progression will be determined. Under the second aim, a case-control study, com- prised of all newly diagnosed individuals with ALS and healthy controls, will determine the presence of geospa- tial clusters of ALS in State of Michigan. The proposed research is innovative, in the applicant’s opinion, be- cause it represents a substantive departure from the status quo by explicitly identifying how persistent organic pollutants alter ALS disease expression and how geospatial factors, such as persistent environmental pollu- tants, alter ALS susceptibility which will pave the way for improved pathophysiologic studies on ALS. New re- search horizons are expected to become attainable as a result. The proposed research is significant, because it will identify factors that can mitigate the risk of developing ALS and furthermore guide future studies on new pathophysiologic mechanisms of ALS. Ultimately, such knowledge has the potential to improve the pathophys- iologic understanding of ALS and other neurodegenerative diseases.

项目摘要/摘要了解环境暴露如何影响发展和临床有根本的差距肌萎缩性侧索硬化症（ALS）的表达。持续存在这一差距代表着一个重要的问题，因为直到填充为止，请了解特定的环境毒素如何影响病理生理 ALS（1）阻碍了描述ALS机制的能力，从而限制了治疗机会和（2）防止从环境中删除可修改的风险因素。长期目标是确定环境毒素对ALS的遗传敏感性和发病机理的影响，将我们的数据背景化支持国家ALS注册中心，并促进治疗和生物标志物发现。总体目标此应用是确定与ALS疾病表达相关的持续性有机污染物。中心假设是，持续的有机污染物改变了ALS的事件和疾病因素，例如生存 al。拟议研究的理由是发现和描述环境毒品的影响 INS上的ALS可以识别可改变的疾病风险，也可以告知我们对疾病的病情的理解生理。在强大的初步数据的指导下，该假设将通过追求两个具体目标来检验：1）确定暴露于持续的有机污染物如何改变随后的患者ALS疾病表达在密歇根大学ALS诊所； 2）扩大对ALS和环境暴露的评估全州以确定ALS的地理空间簇是否发生在密歇根州，并将其与已知的环境污染地点。在第一个目标下，环境暴露的影响 - 通过一份详细的问卷与血液中持续的有机污染物水平结合在一起 - 将确定设定，生存和疾病进展。在第二个目标下，一项案例对照研究，受ALS和健康对照组的所有新诊断的个体珍视，将决定存在Geospa- 密歇根州ALS的tial集群。申请人认为，拟议的研究具有创新性因为它通过明确识别持久性有机物的方式来代表与现状的实质性不同污染物改变ALS疾病表达以及地理空间因素如何，例如持续的环境粉 Tant，改变ALS的敏感性，这将为改善ALS的病理生理研究铺平道路。新的重新搜索范围预计将因此可以实现。拟议的研究很重要，因为它将确定可以减轻开发ALS的风险的因素，并指导未来的新研究 ALS的病理生理机制。最终，这种知识有可能改善病理局的潜力对ALS和其他神经退行性疾病的研究理解。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A 2020 centenary perspective on neuromuscular disorders.

2020 年神经肌肉疾病百年展望。

DOI：
10.1136/jnnp-2020-324327
发表时间：
2020
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
0
作者：
Goutman,StephenA;Callaghan,BrianChristopher;Feldman,Eva
通讯作者：
Feldman,Eva

Tofacitinib Suppresses Natural Killer Cells In Vitro and In Vivo: Implications for Amyotrophic Lateral Sclerosis.

DOI：
10.3389/fimmu.2022.773288
发表时间：
2022
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Figueroa-Romero C;Monteagudo A;Murdock BJ;Famie JP;Webber-Davis IF;Piecuch CE;Teener SJ;Pacut C;Goutman SA;Feldman EL
通讯作者：
Feldman EL

Diagnosis and Clinical Management of Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders.

DOI：
10.1212/con.0000000000000535
发表时间：
2017-10-01
期刊：
Continuum (Minneapolis, Minn.)
影响因子：
0
作者：
Goutman, Stephen A
通讯作者：
Goutman, Stephen A

Voicing the Need for Amyotrophic Lateral Sclerosis Environmental Research.

DOI：
10.1001/jamaneurol.2020.0051
发表时间：
2020-05-01
期刊：
JAMA neurology
影响因子：
29
作者：
Goutman SA;Feldman EL
通讯作者：
Feldman EL

Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis.

DOI：
10.1016/s1474-4422(21)00414-2
发表时间：
2022-05
期刊：
LANCET NEUROLOGY
影响因子：
48
作者：
Goutman, Stephen A.;Hardiman, Orla;Al-Chalabi, Ammar;Chio, Adriano;Savelieff, Masha G.;Kiernan, Matthew C.;Feldman, Eva L.
通讯作者：
Feldman, Eva L.