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：
10042289
负责人：
Jason R Cannon
金额：
$ 22.4万
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 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10042289
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（影响全球约 500 万人），其原因是迄今为止，许多罕见的暴露已导致多巴胺（DA）神经元的选择性死亡。作为危险因素进行了研究，但没有一个与 PD 明确相关。从动物研究到临床试验的成功，这些差距表明该领域的差距非常小。大多数PD研究在单一的假设上检验了动物模型的严重缺陷。然而，模型系统在增强研究结果的强度方面具有明显的优势。 R21 旨在通过了解物种差异来推进该领域的发展。 17-039（神经退行性变的比较生物学）通过测试三个方面的 PD 相关神经退行性变本着 R21 的精神，该提案利用了高风险/高风险的动物模型系统。奖励方法，将测试新的风险因素，以增进对帕金森病生物学的理解。全氟烷基物质和多氟烷基物质 (PFAS) 是广泛存在的环境污染物，已被作为发育毒物进行研究，但我们的初步信息很少涉及长期神经毒性。线虫和两栖动物模型的机制和神经病理学数据表明，接触 PFAS、特别是全氟辛烷磺酸 (PFOS) 会诱导选择性 PD 相关的 DAergic 神经毒性。将解决 PFAS 暴露如何导致长期神经系统疾病风险的重要差距。假设：对 PFOS 引起的多巴胺能神经变性的物种特异性反应将会进展重要的是，该假设将在 3 个动物模型系统中进行测试，一致性将加强发现，不一致将识别物种特异性的生物学方面我们将通过两个目标来检验我们的假设： 1. 确定引起 DAergic 神经变性的物种特异性 PFOS 剂量。跨系统协调，以实现具有内部环境相关性的大脑水平。为每个模型系统设置外部应用剂量的剂量水平将使我们能够询问机制目标 2：确定不同物种的神经生物学基础有助于对 PFOS 引起的多巴胺能神经变性的不同敏感性。在这里，我们将确定。神经变性的物种特异性差异可能是选择性多巴胺能关键方面的基础我们将进行表型比较生物学研究。结果数据对于确定：1) 哪种物种最适合 PFOS 至关重要。 2）确定与神经退行性疾病直接相关的致病途径；这些研究将机械地推动该领域远远超出来自物种的神经退行性变的数据。典型的单物种研究。