Neurotoxic and neurodegenerative risks from chronic exposure to metal mixtures in e-cigarette aerosol

项目总结 本项目的主要目标是研究使用一种新的外周生物标志物--金属的可行性 循环脑源性细胞外小泡(EVS)货物--用于评估脑内非侵入性金属沉积 由于暴露在电子烟的气雾剂中。该项目是正在进行的R01的补充，该R01调查 金属暴露和金属代谢紊乱对小鼠的神经毒性、行为和病理影响 暴露在电子烟气雾剂中。 这份补充材料的候选人是一名海地裔美国公民。她毕业于巴纳德学院 获得环境科学学士学位，辅修生物学。她报名参加我们的MS计划，地址是 哥伦比亚大学将在2022年秋季增加黑人女性在科学界的代表性，这是 尤其缺乏。对于她的研究和培训，她将得到Diane Re博士和Markus Hilpert博士的指导， 家长资助金的MPI，她将从Ana Navas-Acien博士那里获得额外的指导，她是 哥伦比亚大学的电子烟工作组。在提议的项目中，候选人将(1)确定 血-脑电动车中的金属含量是否是电子烟暴露和脑金属的纵向生物标志物 在接触电子烟气雾剂后消除，(2)调查大脑EV金属水平是否可以用于 非侵入性推断电子烟暴露小鼠大脑中的金属负荷，以及(3)探索基因 对帕金森氏病(PD)的易感性改变了大脑EV的金属含量。 通过建议的分析，应聘者将获得以下方面的经验和技能：1)使用新型电动汽车 研究电子烟金属暴露对神经退行性疾病影响的生物标志物，2) 新生物标志物数据的统计分析；3)环境暴露的动物模型训练，以及4) 了解电子烟接触有毒金属对脑内金属稳态的影响机制 和神经退行性疾病。应聘者还将接受正式培训，通过我们的 在正常学年期间提供理科硕士课程。候选人和导师将每周会面一次，进行培训和 讨论进展情况。 该项目可以验证第一个与大脑相关的外周生物标记物来预测受试者的脑金属负荷 暴露在电子烟气雾剂中。基于这项研究，脑EV金属负荷可能成为一个已确立的生物标志物 尿布和二手接触的个体神经毒性风险。这项拟议的研究也具有重要意义 对减少电子烟气雾剂暴露的不良影响的干预研究的影响。最后，通过 为理科硕士学生提供高级技能、培训和实验室研究机会 将重点放在毒理学上，这个项目将增强我们哥伦比亚大学研究团队的多样性 在毒理学和环境健康科学领域的道路。

Project summary The main objective of this project is to investigate the feasibility of using a novel peripheral biomarker—the metal cargo of circulating brain-derived extracellular vesicles (EVs)—to assess non-invasively metal deposition in brain due to e-cigarette aerosol exposure. This project is a supplement to an ongoing R01, which investigates the neurotoxic, behavioral and pathological consequences of metal exposure and metal dyshomeostasis in mice exposed to e-cigarette aerosol. The candidate for this supplement is a US citizen of Haitian descent. She graduated from Barnard College with a B.A. degree in Environmental Science and a minor in Biology. Her enrollment into our MS program at Columbia University in the Fall of 2022 will increase the representation of Black women in science, which is particularly lacking. For her research and training, she will be mentored by Drs. Diane Re and Markus Hilpert, MPIs of the parent grant, and she will receive additional mentorship from Dr. Ana Navas-Acien who is part of the e-cigarette working group at Columbia University. In the proposed project, the candidate will (1) determine whether metal content in blood brain-EVs is a longitudinal biomarker of e-cigarette exposure and brain metal elimination upon exposure to e-cigarette aerosol, (2) investigate whether brain EV metal levels can be used to non-invasively infer metal burden in the brain of e-cigarette exposed mice, and (3) explore whether genetic susceptibility to Parkinson's disease (PD) modifies brain EV metal content. Through the proposed analyses, the candidate will gain experience and skills in: 1) the use of novel EV biomarkers to study the effects of metal exposure from e-cigarette use on neurodegenerative disease, 2) statistical analysis of the novel biomarker data; 3) training in animal models of environmental exposures, and 4) understanding the mechanisms of toxic metal exposure from e-cigarette use on metal homeostasis in the brain and neurodegenerative disease. The candidate will also receive formal training by taking courses through our MS program during the regular school year. The candidate and mentors will meet once a week for training and to discuss progress. This project could validate the first brain-relevant peripheral biomarker to predict brain metal load of subjects exposed to e-cigarette aerosol. Based on this study, brain EV metal load could become an established biomarker of individual neurotoxic risk for vapers and second-hand exposure. The proposed research has also significant implications for intervention studies to reduce adverse effects of e-cigarette aerosol exposure. Finally, by providing advanced skills, training and laboratory research opportunities to a Master of Science student with focus in toxicology, this project will enhance diversity in our research team at Columbia University and down the road in the fields of toxicology and environmental health sciences.