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.

帕金森氏病（PD）是一种使人衰弱的运动障碍（影响了约500万个世界范围）多巴胺（DA）神经元的选择性死亡。迄今为止，许多很少遇到的暴露被调查为危险因素，但没有一个与PD明确相关的。此外，理论的翻译在成功的临床试验中，在动物研究中有望很差。这些领域的差距暗示 PD研究中动物模型利用的严重弱点。大多数PD研究在单个中检验假设模型系统。但是，在增加发现的力量方面具有明显的优势和通过了解物种差异来推进该领域。该R21旨在对PAR高度响应 17-039（神经退行性的比较生物学）通过在三个中测试PD-元素神经变性系统发育多样的动物模型系统。本着R21的精神，该提案利用了高风险/高奖励方法，将测试新的风险因素以提高对PD生物学的理解。每种和多氟烷基物质（PFA）是已广泛的环境污染物被调查为发育有毒物质，几乎没有关于长期神经毒性的信息。我们的初步线虫和两栖模型中的机械和神经病理学数据表明，暴露于PFA，尤其是全氟辛烷磺酸盐（PFO）诱导选择性PD相关的DAERGIC神经毒性。这个项目将解决有关PFAS暴露如何导致长期神经疾病风险的重要差距。我们将测试假设：对PFOS诱导的多巴胺能神经变性的规格特异性响应将推进对PD生物学的理解。重要的是，该假设将在3个动物模型系统中进行检验，一致性将加强发现，而不一致将确定物种特异性的生物学方面对环境引起的神经变性的敏感性。我们将通过两个目标来检验我们的假设：目标 1。确定诱导Daergic神经退行性的特定规范剂量。 PFO剂量将是跨系统协调以达到具有环境相关性的大脑水平。内部协调为每个模型系统设置外部施加剂量的剂量水平将使我们能够询问机械在可比的侮辱下的假设；目标2。确定跨物种的神经生物学基础有助于对PFOS诱导的多巴胺能神经退行性变化的差异敏感性。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的关键方面的基础 PFOS暴露引起的神经毒性。我们将进行比较生物学研究，这些研究都是表型和机械。最终数据对确定至关重要：1）哪些物种最适合PFO 神经变性研究； 2）确定哪种致病途径与跨物种的神经变性。这些研究将机械地将领域推进到远离数据典型的单物种研究。