Quantitative Metabolomic Analysis of Chronic Exposures to Environmental Toxicants

描述(由申请人提供) 过去20年收集的数据表明，长期接触持久性环境毒物，包括多氯联苯和氯化有机杀虫剂，会增加患神经退行性疾病的风险，如帕金森氏病(PD)。最近的研究表明，这些毒物导致细胞内多巴胺水平升高，氧化应激增加，最终导致多巴胺能细胞死亡，这是帕金森病的一个标志。这项提案的主要目标是通过教学学习、指导研究和多学科提案开发相结合的方式，迅速推进候选人在该领域的职业生涯。候选人库尔特·D·彭内尔是佐治亚理工学院土木与环境工程学院环境工程副教授。这项职业发展计划包括生物信息学、高级光谱学和神经毒理学方面的课程，建立在他在科学和工程方面的培训、地下系统中污染物传输和修复的研究、分析技能以及在埃默里大学神经病学系正在进行的休假的基础上。拟议的活动将在佐治亚理工学院和埃默里大学进行，候选人在那里拥有客座副教授的头衔。这项拟议研究的基本假设是，氧化应激和代谢组特征的生物标记物可以与慢性毒物暴露和神经退行性疾病相关。在Emory临床生物标记物实验室主任Dean P.Jones教授的指导下，该研究项目的具体目标是：1)量化氯化有机化合物在死后人体组织和暴露于C57BL/6小鼠中的积累和分布；2)利用已建立的高效液相色谱方法和H1-核磁共振(核磁共振)谱评估代谢紊乱和氧化应激；以及3)建立和评估基于离子交换液相色谱和傅里叶变换离子回旋共振质谱仪(FT-ICR MS)的高通量定量代谢组谱方法。彭内尔博士的职业目标是在环境代谢组学方面建立一个积极的研究计划，在调查环境毒物慢性暴露的多学科研究团队中发挥不可或缺的作用，并在促进环境工程和生物医学科学之间的联系方面成为领导者。 相关性：该建议与公共健康相关，因为它将促进我们对长期暴露于环境毒物和神经退行性疾病之间的关系的理解，提供快速筛查氧化应激和不利代谢特征的定量方法，并为早期发现和干预提供可能性。

DESCRIPTION (provided by applicant) Data compiled over the last two decades indicate that chronic exposure to persistent environmental toxicants, including polychlorinated biphenyls (PCBs) and chlorinated organic insecticides, increases the risk of developing neurodegenerative disease, such as Parkinson's disease (PD). Recent studies suggest that these toxicants contribute to elevated intracellular dopamine levels, increased oxidative stress, and ultimately dopaminergic cell death, a hallmark of PD. The primary objective of this proposal is to rapidly advance the career of the candidate in this field through a combination of didactic learning, mentored research, and multi-disciplinary proposal development. The candidate, Kurt D. Pennell, is an Associate Professor of Environmental Engineering in the School of Civil & Environmental Engineering at the Georgia Institute of Technology. The career development plan, which includes coursework in bioinformatics, advanced spectroscopy and neurotoxicology, builds upon his training in science and engineering, research on contaminant transport and remediation in subsurface systems, analytical skills, and on-going sabbatical in the Department of Neurology at Emory University. The proposed activities will be carried out at Georgia Tech and Emory, where the candidate holds the title of visiting Associate Professor. The underlying hypothesis of the proposed research is that biomarkers of oxidative stress and metabolomic profiles can be correlated to chronic toxicant exposures and neurodegenerative disease. Under the mentorship of Dean P. Jones, Professor and Director of the Emory Clinical Biomarkers Laboratory, the specific aims of the research project are to: 1) Quantify the accumulation and distribution of chlorinated organic compounds in postmortem human tissue and exposed C57BL/6 mice, 2) Assess metabolic disruption and oxidative stress using established HPLC methods and H1-nuclear magnetic resonance (NMR) spectroscopy, and 3) Develop and evaluate a high-throughput, quantitative metabolomic profiling method based on coupled ion exchange liquid chromatography and Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS). Dr. Pennell's career goals are to establish an active research program in environmental metabolomics, play an integral role in multi-disciplinary research teams investigating chronic exposures to environmental toxicants, and to be a leader in fostering linkages between environmental engineering and biomedical sciences. Relevance: The proposal is relevant to public health because it will advance our understanding of the relationship between chronic exposure to environmental toxicants and neurodegenerative disease, provide quantitative methods to rapidly screen for oxidative stress and adverse metabolic profiles, and offer the possibility for early detection and intervention.