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

项目摘要 本计画的主要目的是探讨使用一种新颖的周边式生物标记物--金属 循环脑源性细胞外囊泡（EV）的货物-评估脑中的非侵入性金属沉积 是因为暴露在电子烟烟雾中该项目是对正在进行的R 01的补充，R 01调查了 小鼠金属暴露和金属稳态异常的神经毒性、行为和病理后果 暴露在电子烟烟雾中 该补充的候选人是海地血统的美国公民。她毕业于巴纳德学院 毕业学士学位环境科学学士学位，副修生物学。她参加了我们的硕士课程， 哥伦比亚大学将在2022年秋季增加黑人女性在科学领域的代表性， 尤其缺乏。对于她的研究和培训，她将由黛安·雷博士和马库斯·希尔珀特博士指导， 她将获得Ana Navas-Acien博士的额外指导，Ana Navas-Acien博士是 哥伦比亚大学的电子烟工作组。在建议的项目中，候选人将（1）确定 血脑-EV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 消除暴露于电子烟气雾剂，（2）研究是否可以使用脑EV金属水平， 非侵入性地推断暴露于电子烟的小鼠大脑中的金属负荷，以及（3）探索是否遗传 帕金森病（PD）的易感性改变了脑EV金属含量。 通过这些分析，候选人将获得以下方面的经验和技能：1）使用新型电动汽车 生物标志物，以研究电子烟使用中的金属暴露对神经退行性疾病的影响，2） 新生物标志物数据的统计分析; 3）环境暴露动物模型的培训，以及4） 了解电子烟使用中有毒金属暴露对大脑金属稳态的影响机制 和神经退行性疾病。候选人还将通过参加我们的课程， MS课程在常规学年。候选人和导师将每周会面一次进行培训， 讨论进展 该项目可以验证第一个脑相关外周生物标志物来预测受试者的脑金属负荷 暴露在电子烟烟雾中基于这项研究，脑EV金属负荷可能成为一个既定的生物标志物 电子烟和二手烟暴露的个体神经毒性风险。这项研究也具有重要意义。 对干预研究的影响，以减少电子烟气雾剂暴露的不良影响。最后通过 提供先进的技能，培训和实验室研究的机会，以科学的学生与硕士 该项目将加强我们在哥伦比亚大学和下 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.