Vesicular monoamine transporter 2 as a mediator of PBDE neurotoxicity

描述（由申请人提供） 人们对多溴联苯醚的健康风险表示关切，特别是考虑到其在环境中普遍存在的持久性，以及其在环境和人体组织中的含量明显增加。五溴二苯醚混合物DE 71已被证明可抑制囊泡单胺转运蛋白2（VMAT 2）对多巴胺的螯合作用，并产生氧化应激。VMAT2是胞质多巴胺的关键介质，调节神经毒性反应物质的积累和代谢。它已被公认，增强氧化应激有助于帕金森病（PD）的发病机制。虽然PD的病因不明，但流行病学证据表明环境与PD的发展之间存在密切联系。由于DE 71改变多巴胺储存，这表明VMAT 2可能是DE 71神经毒性的推定靶点。随着我们对环境在PD中所起作用的了解的增加，更好地了解大脑中受环境化合物影响的分子机制将非常重要。该提案将研究通过改变VMAT2破坏多巴胺处理对DE 71介导的多巴胺神经元变性的影响。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在严格的研究环境中的参与来实现，他将与他的导师和共同导师互动，这对他获得先进的实验技术和理解成功的主要研究者的日常责任至关重要。毒理学和神经科学，研究技术，实验室管理的综合知识，以及在学术界取得成功所需的承诺，他将获得作为一名实习生将立即应用，因为他承担建立自己的实验室的任务。这些技能不仅将促进无障碍过渡到独立，他们还将增强候选人的能力，以监督一个成功的实验室，目的是阐明环境在神经退行性疾病中的作用。

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.