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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/R00 提案寻求支持开发一项独立研究计划，旨在解决与全氟辛烷磺酸 (PFOS) 作为潜在风险因素的问题多巴胺能细胞损失。多氟烷基物质（PFAS）在消防设备、不粘炊具、地毯等，因其独特的拒油拒水能力。这些化学物质构成由于其半衰期长和抵抗环境影响的能力，直接威胁环境健康由于其强大的碳氟键而降解。广泛的存在和巨大的知识差距与神经毒性作用和潜在机制以及较大比例的散发病例有关主要的神经退行性疾病迫切需要研究此类化合物。我们的初步对秀丽隐杆线虫中 PFOS 的研究表明，DA 具有神经毒性、线粒体含量减少和线粒体含量增加。活性氧（Sammi 等人，2019）。这些影响是帕金森病的特征表现 (PD)，90% 的散发性 PD 病例的病因很大程度上未知。根据秀丽隐杆线虫的初步数据线虫，显示 DA 细胞因全氟辛烷磺酸而损失，我将发展诱导多能干细胞方面的专业知识。一个将采取包括体内和体外模型在内的多管齐下的方法来进一步确定神经毒性和神经发育缺陷，重点阐明线粒体和 GSH 如何延伸他们在神经病理学中的作用。传统上，毒性评估很大程度上依赖于基于终点的研究，而机械方面仍然很大程度上未被充分研究。化学物质的有害影响会在一段时间内出现时间以病理形式出现，这是机械改变或畸变的集体结果。所以，识别最终导致神经毒性的一系列生化事件对于定义不良反应至关重要结果途径（AOP）。已确定的机制保证了设计干预措施、机制的能力评估类似化合物并合成更安全的化合物。我的方法包括体外和体内系统来阐明 PFOS 的神经毒性作用。与 AOP 相关的信息将作为机制用于同类化合物 (PFAS) 之间比较评估的终点/标记，促进结构-活性关系的推导。总之，我将画出 PFOS 的体内、体外特征介导的多巴胺毒性。此外，详细的职业发展计划需要课程作业，学习新技术/模型系统、代表和出席科学会议以及来自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，将有助于开发与导师实验室不同的科学焦点，并促进独立的研究生涯。