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PFOS-induced dopaminergic neurodegeneration across nematode, amphibian, and rodent models

线虫、两栖动物和啮齿动物模型中全氟辛烷磺酸诱导的多巴胺能神经变性

基本信息

批准号：
10241311
负责人：
Jason R Cannon
金额：
$ 18.52万
依托单位：
PURDUE UNIVERSITY
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：
2020-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241311
关键词：
Address Affect Amphibia Animal Model Animals Big Data Biological Biological Models Biology Brain Cell physiology Cessation of life Clinical Trials Comparative Biology Comparative Study Coupled Data Detection Developmental Toxicant Dose Environmental Pollution Exposure to Goals Health Hypothalamic structure Link Measures Modeling Movement Disorders Nematoda Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurologic Neurotransmitters Outcome Parkinson Disease Pathogenesis Pathogenicity Pathway interactions Phase Phenotype Phylogenetic Analysis Plasma Rana Research Research Project Grants Risk Risk Factors Rodent Rodent Model Role System Testing Therapeutic Tissues Translations Ursidae Family bioaccumulation comparative disorder risk dopaminergic neuron dosage high reward high risk innovation nervous system disorder neurobehavioral neuropathology neurotoxicity neurotransmission novel oxidative damage perfluorooctane sulfonate pituitary thyroid axis protein aggregation resilience response species difference success

项目摘要

Parkinson's disease (PD) is a debilitating movement disorder (affecting ~5 million world‐wide) resulting from selective death of dopamine (DA) neurons. To date, numerous rarely encountered exposures have been investigated as risk factors, but none have been clearly linked to PD. Further, the translation of therapeutics that are promising in animal studies to successful clinical trials has been very poor. These gaps in the field suggest serious weaknesses in the utilization of animal models in PD research. Most PD studies test hypotheses in single model systems. However, there are clear advantages with respect to increasing the strength of the findings and advancing the field through understanding species differences. This R21 aims to be highly responsive to PAR‐ 17‐039 (Comparative Biology of Neurodegeneration) by testing PD‐relevant neurodegeneration across three phylogenetically diverse animal model systems. In the spirit of an R21, the proposal utilizes high risk/high reward approaches, where novel risk factors will be tested to advance the understanding of the biology of PD. Per‐ and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants that have been investigated as developmental toxicants, with little information on long‐term neurotoxicity. Our preliminary mechanistic and neuropathology data in nematode and amphibian models suggest that exposure to PFAS, especially perfluorooctane sulfonate (PFOS) induces selective PD‐relevant, DAergic neurotoxicity. This project will address an important gap on how PFAS exposure leads to long‐term neurological disease risk. We will test the hypothesis: that species‐specific responses to PFOS‐induced dopaminergic neurodegeneration will advance understanding of the biology of PD. Importantly, the hypothesis will be tested across 3 animal model systems, where concordance will strengthen findings, and discordance will identify biological aspects of species‐specific sensitivity to environmentally‐induced neurodegeneration. We will test our hypothesis through two aims: Aim 1. To identify species specific‐PFOS doses that induce DAergic neurodegeneration. PFOS doses will be harmonized across systems to achieve brain levels that bear environmental relevance. Harmonization of internal dose levels to set external applied dosages for each model system will allow us to interrogate mechanistic hypothesis under comparable insults; Aim 2. Identify neurobiological underpinnings across species that contribute to differential sensitivity to PFOS‐induced dopaminergic neurodegeneration. Here, we will identify species‐specific differences in neurodegeneration that may underlie critical aspects of selective dopaminergic neurotoxicity induced by PFOS exposure. We will conduct comparative biology studies that are both phenotypic and mechanistic. Resultant data will be critical in determining: 1) Which species is best suited to PFOS neurodegeneration studies; 2) Identifying which pathogenic pathways directly correlate with neurodegeneration across species. These studies will mechanistically advance the field far beyond data from typical single‐species studies.

帕金森病（PD）是一种使人衰弱的运动障碍（全球约有500万人受到影响）