Vesicular monoamine transporter 2 as a mediator of PBDE neurotoxicity

囊泡单胺转运蛋白 2 作为 PBDE 神经毒性的介质

基本信息

批准号：
8282930
负责人：
William Michael Caudle
金额：
$ 24.23万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-03 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8282930
关键词：
Academia Affect Biochemical Biological Biological Models Biology Brain Cells Cessation of life Cognitive Corpus striatum structure DNA Development Dopamine Environment Environmental Pollution Epidemiology Etiology Evaluation Exposure to Functional disorder Generations Goals Guidelines Health Human In Vitro Knowledge Laboratories Laboratory Study Lipids Mediating Mediator of activation protein Mentors Metabolism Molecular Neurodegenerative Disorders Neurosciences Research Oxidative Stress Parkinson Disease Pathogenesis Pentas Pesticides Play Polychlorinated Biphenyls Proteins Proteomics Reactive Oxygen Species Research Research Personnel Research Technics Resistance Risk Risk Assessment Risk Factors Role Secondary to Signal Pathway Substantia nigra structure Techniques Toxic Environmental Substances Toxic effect Toxicology critical period dopamine system dopaminergic neuron exposed human population human tissue in vivo insight interest lipophilicity neurodevelopment neurotoxic neurotoxicity pars compacta phenyl ether protein protein interaction skills uptake vesicular monoamine transporter 2

项目摘要

DESCRIPTION (provided by applicant) Concerns over the health risks associated with polybrominated diphenyl ethers (PBDEs) have been raised, especially given their ubiquitous environmental persistence and appreciable increases in their levels, both in the environment and human tissue. The penta-PBDE mixture, DE 71 has been demonstrated to inhibit the sequestration of dopamine by the vesicular monoamine transporter 2 (VMAT2) and generate oxidative stress. VMAT2 is a key mediator of cytosolic dopamine, regulating the accumulation and metabolism to neurotoxic reactive species. It has been well established that enhanced oxidative stress contributes to Parkinson's disease (PD) pathogenesis. Although the etiology of PD is unknown, epidemiological evidence has demonstrated a strong association between the environment and the development of PD. As DE 71 alters dopamine storage, this suggests that VMAT2 may be a putative target for DE 71 neurotoxicity. As our knowledge of the role that the environment plays in PD grows it will be important to gain a better understanding of the molecular mechanisms within the brain that are affected by environmental compounds. This proposal will examine the influence that disruption of dopamine handling by alteration of the VMAT2 has on DE 71-mediated degeneration of dopamine neurons. Furthermore, it will examine potential mechanism(s) by which DE 71 disrupts VMAT2. Completion of this project will be achieved through the candidate's involvement in a rigorous research environment where he will interact with his mentor and co-mentor, which will be critical to his acquisition of progressive experimental techniques and understanding of the daily responsibilities of a successful principle investigator. The comprehensive knowledge of toxicology and neuroscience, research techniques, laboratory management, and the commitment needed to succeed in academia that he will gain as a trainee will be immediately applied as he undertake the task of establishing his own laboratory. Not only will these skills facilitate a seemless transition to independence, they will also augment the candidate's ability to supervise a successful laboratory with the goal of elucidating the role of the environment in neurodegenerative disease.

描述（由申请人提供）人们对与多溴二苯基醚相关的健康风险（PBDE）的担忧已经提高，尤其是考虑到它们在环境和人体组织中的无处不在的环境持久性以及其水平可观的增加。已证明PENTA-PBDE混合物DE 71可以通过囊泡单胺转运蛋白2（VMAT2）抑制多巴胺的固结并产生氧化应激。 VMAT2是胞质多巴胺的关键介体，可调节神经毒性反应性物种的积累和代谢。已经有很好的确定，增强的氧化应激有助于帕金森氏病（PD）发病机理。尽管PD的病因尚不清楚，但流行病学证据表明环境与PD的发展之间存在很强的联系。 DE 71改变了多巴胺的储存，这表明VMAT2可能是DE 71神经毒性的推定目标。随着我们对环境在PD中扮演的作用的了解，更好地了解受环境化合物影响的大脑中的分子机制将很重要。该提案将研究通过改变VMAT2对DE 71介导的多巴胺神经元变性的破坏处理的影响。此外，它将检查DE 71破坏VMAT2的潜在机制。该项目的完成将通过候选人参与严格的研究环境来实现，在那里他将与他的导师和联合学者进行互动，这对于他对渐进实验技术的收购和对成功原则研究者的日常责任的理解至关重要。关于毒理学和神经科学，研究技术，实验室管理以及成功学术界所需的承诺，他将作为一名学员获得的全面知识将在他承担建立自己的实验室的任务时立即应用。这些技能不仅可以促进到独立性的过渡，还将增强候选人监督成功实验室的能力，目的是阐明环境在神经退行性疾病中的作用。