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Elucidation of mitochondrial mechanisms critical to mediating PFAS neurotoxicity

阐明对介导 PFAS 神经毒性至关重要的线粒体机制

基本信息

批准号：
10805097
负责人：
Shreesh Raj Sammi
金额：
$ 24.9万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10805097
关键词：
Address Advisory Committees Analytical Chemistry Animals Antioxidants Biochemical Bioenergetics Biological Biological Models Brain Caenorhabditis elegans Carbon Carpet Carrier Proteins Cell Culture Techniques Cells Characteristics Chemicals Complex DNA Sequence Alteration Data Defect Dependence Derivation procedure Development Development Plans Dopaminergic Cell Dose Environmental Health Equipment Etiology Evaluation Event Feedback Fluorine Future Gene Expression Genes Genetic Genus Hippocampus Goals Half-Life Health Health Benefit Health Hazards Human Impairment In Vitro Individual Industrialization Intervention Knowledge LRRK2 gene Laboratories Learning Light Mediating Mentors Metals Methods Mitochondria Nematoda Nerve Degeneration Neurodegenerative Disorders Neurons Oils Organelles Outcome Oxygen Consumption Parkinson Disease Pathologic Pathology Pathway interactions Patients Pesticides Phase Poly-fluoroalkyl substances Program Development Protein Import Protons Public Health Publishing Reactive Oxygen Species Research Resistance Respiration Risk Risk Factors Role Series Soil Stains Structure Structure-Activity Relationship Sulfonic Acids System Techniques Teratogenic effects Testing Time Toxic effect Training Transgenic Organisms United States National Institutes of Health Validation Water Water Pollutants Whole Organism Work adverse outcome alpha synuclein anthropogenesis career career development comparative dopamine toxicity dopaminergic neuron experimental study exposed human population gene environment interaction in vitro Model in vivo induced pluripotent stem cell knock-down meetings neurodevelopmental effect neuropathology neurotoxic neurotoxicity overexpression perfluorooctane sulfonate programs response skill acquisition sporadic Parkinson&apos s Disease substance use therapy design toxicant toxicant interaction translational impact uptake

项目摘要

Project Summary: This NIH K99/R00 proposal seeks support for the development of an independent research program aimed at addressing the questions pertaining to perfluorooctane sulfonic acid (PFOS) as a potential risk factor dopaminergic cell loss. Polyfluoroalkyl substances (PFAS) have important usage in firefighting equipment, nonstick cookware, carpets, etc. due to their unique capabilities to repel oil and water. These chemicals pose an immediate environmental health threat due to their protracted half-life and ability to resist environmental degradation, owing to its strong carbon-fluorine bond. The extensive presence and huge gaps in knowledge pertaining to neurotoxic effects and underlying mechanisms alongside a larger percentage of sporadic cases in major neurodegenerative disorders compel the dire need to investigate such compounds. Our preliminary studies on PFOS in C. elegans have shown DA neurotoxicity, reduction in mitochondrial content, and increased reactive oxygen species (Sammi et al., 2019). These effects are characteristic manifestations in Parkinson’s disease (PD), with cause largely unknown in 90% of sporadic PD cases. In light of the preliminary data in Caenorhabditis elegans, showing DA cell loss in response to PFOS, I will develop expertise in Induced pluripotent stem cells. A multi-pronged approach comprising of in vivo and in vitro models will be conducted to further identify neurotoxic and neurodevelopmental defects with a larger focus to elucidate how mitochondria and GSH extend their role in neuropathology. Conventionally, toxicity evaluation relies heavily on end-point based studies, while mechanistic aspects remain largely understudied. Deleterious effects of the chemicals appear over the span of time in the form of pathologies, which is a collective result of mechanistic alterations or aberrations. Therefore, identification of the series of biochemical events culminating in neurotoxicity is vital to define the Adverse outcome pathway (AOP). The identified mechanisms warrant the ability to design interventions, mechanistic assessment of similar compounds and synthesis of safer compounds. My approach consists of in vitro and in vivo systems to elucidate the neurotoxic effects of PFOS. Information pertaining to AOPs will serve as mechanistic endpoints/markers for comparative evaluation amongst a similar class of compounds (PFAS), facilitating derivation of the structure-activity relationship. In summary, I will draw an in vivo, in vitro signature of PFOS mediated Dopamine toxicity. Additionally, a detailed career development program entailing coursework, learning new techniques/model systems, representation and attendance at scientific meetings and feedback from the advisory committee has been constructed to help the candidate. My plan includes mentored training in critical new techniques/model systems, combined with my existing expertise that will enable the development of a scientific focus distinct from the mentor’s lab and promoting an independent research career.

项目概要： NIH K99/R 00提案寻求对独立研究计划发展的支持，处理与作为潜在风险因素的全氟辛烷磺酸有关的问题多巴胺能细胞丧失多氟烷基物质（PFAS）在消防器材中有重要用途，不粘炊具、地毯等，因为它们具有独特的拒油拒水的能力。这些化学物质构成了由于其半衰期较长，且具有抵抗环境污染能力，降解，由于其强的碳-氟键。知识的广泛存在和巨大差距关于神经毒性作用和潜在机制，以及在主要的神经变性疾病迫使迫切需要研究这些化合物。我们的初步 C.中全氟辛烷磺酸的研究线虫显示DA神经毒性，线粒体含量减少，活性氧物质（Sammi等人，2019年）。这些影响是帕金森病的特征性表现 (PD)90%的散发性PD病例病因不明。根据小杆线虫的初步数据 elegans，显示DA细胞损失响应PFOS，我将开发诱导多能干细胞的专业知识。一将进行包括体内和体外模型的多管齐下的方法，以进一步确定神经毒性和神经发育缺陷，重点是阐明线粒体和GSH如何延伸在神经病理学中的作用传统上，毒性评价严重依赖于基于终点的研究，而机械方面的问题在很大程度上仍然没有得到充分的研究。这些化学品的有害影响在整个时间以病理的形式存在，这是机械性改变或失常的集体结果。因此，我们认为，确定最终导致神经毒性的一系列生化事件对于确定不良反应至关重要。结果途径（AOP）。所确定的机制保证了设计干预措施的能力，类似化合物的评估和更安全化合物的合成。我的方法包括体外和体内系统，以阐明全氟辛烷磺酸的神经毒性效应。与AOP相关的信息将作为终点/标志物，用于在类似类别的化合物（PFAS）中进行比较评价，构效关系的推导。总之，我将绘制PFOS的体内、体外特征图，介导的多巴胺毒性。此外，一个详细的职业发展计划，需要课程，学习新技术/模型系统，代表和出席科学会议，并从设立咨询委员会是为了帮助候选人。我的计划包括指导培训，关键的新技术/模型系统，结合我现有的专业知识，将使发展与导师的实验室不同的科学重点，并促进独立的研究生涯。