Mechanisms of Methylmercury Induced Neuronal Toxicity

 描述(由申请人提供)：甲基汞(MeHg)是一种强烈的神经毒素，对发育中和成熟的中枢神经系统(CNS)都有影响，明显不分青红皂白地破坏多种体内平衡途径。然而，遗传和环境修饰物对与人类暴露相关的神经毒性具有显著的变异性。这项研究的长期目标是阐明甲基汞神经毒性的基础，并确定基于机制的神经保护策略，以减少人类接触甲基汞的风险。在这里，我们提出了一种多方面的方法，结合了强大的神经遗传学模型系统、基于人类的细胞和遗传学方法来提供影响甲基汞暴露易感性的新的疾病改善策略，并能够从机械上洞察改变特定神经谱系对甲基汞神经毒性的敏感性的遗传途径。具体来说，我们将 测试这一假设，即改变对甲基汞诱导的神经毒性易感性的遗传路径将表现出神经谱系和发育阶段依赖的活动。在特定的目标1中，我们将通过RNAi筛选甲基汞诱导的线虫发育过程中多巴胺能(DAer能)和谷氨酸能(GLU能)神经毒性的遗传修饰物。在特定目标2中的研究将比较和对比人类黑质DAR能和皮质GLU能神经谱系的甲基汞神经毒理学结果。最后，在具体目标3中，我们将评估遗传途径改变甲基汞神经毒性的机制。这种高度互动的实验设计带来了创新和互补的专业知识，以评估共享的遗传网络，通过从线虫到人类的翻译外推来减轻甲基汞诱导的毒性。

 DESCRIPTION (provided by applicant): Methylmercury (MeHg) is a potent neurotoxin affecting both the developing and mature central nervous system (CNS) with apparent indiscriminate disruption of multiple homeostatic pathways. However, genetic and environmental modifiers contribute significant variability to neurotoxicity associated with human exposures. The long-term goal of this research is to elucidate the basis of MeHg neurotoxicity and to identify mechanistic- based neuroprotective strategies to mitigate human MeHg exposure risk. Here, we propose a multifaceted approach, combining powerful neurogenetic model systems, human-based cellular and genetic approaches to provide novel disease modifying strategies impinging on MeHg exposure vulnerability, and enable mechanistic insight into genetic pathways that modify sensitivity of specific neural lineages to MeHg-induced neurotoxicity. Specifically, we will test the hypothesis that genetic pathways that alter susceptibility to MeHg-induced neurotoxicity will display neural lineage- and developmental stage-dependent activity. In Specific Aim 1, we will screen for genetic modifiers of developmental MeHg-induced dopaminergic (DAergic) and glutamatergic (GLUergic) neurotoxicity in the nematode, C. elegans, by RNAi. Studies in Specific Aim 2 will compare and contrast MeHg neurotoxicological outcomes in human nigral DAergic versus cortical GLUergic neural lineages. Finally, in Specific Aim 3, we will evaluate mechanisms by which genetic pathways modify MeHg neurotoxicity. This highly interactive experimental design brings to bear innovative and complementary expertise to assess shared genetic networks attenuating MeHg-induced toxicity with translational extrapolation from the nematode to humans.