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

• 批准号: 10301852
• 负责人: Shreesh Raj Sammi
• 金额: $ 10.48万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301852
• 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; 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; base; 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; programs; response; skills; substance use; therapy design; toxicant; toxicant interaction; translational impact; uptake

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) 在消防设备中具有重要用途， 不粘炊具、地毯等由于其独特的防油和防水能力，这些化学物质会产生化学反应。 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 降解，归因于其强大的碳氟键的广泛存在和巨大的知识空白。 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。 对秀丽隐杆线虫中 PFOS 的研究表明，DA 具有神经毒性、线粒体含量减少以及线粒体含量增加。 活性氧（Sammi et al., 2019）这些影响是帕金森病的特征表现。 (PD)，根据秀丽隐杆线虫的初步数据，90% 的散发性 PD 病例的病因很大程度上未知。 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 A 方面的专业知识。 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 传统上，毒性评估很大程度上依赖于基于终点的研究。 化学物质的有害影响在很大程度上仍未得到充分研究。 时间以病理形式出现，这是机械改变或畸变的集体结果。 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。 评估相似的化合物和合成更安全的化合物我的方法包括体外和体内。 阐明 PFOS 神经毒性作用的系统将作为机制的相关信息。 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，我将绘制 PFOS 的体内、体外特征。 此外，还需要制定详细的职业发展计划，包括课程作业， 学习新技术/模型系统、代表和出席科学会议以及来自 成立咨询委员会是为了帮助候选人 我的计划包括导师培训。 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。