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Mechanisms of Methylmercury Induced Neuronal Toxicity

甲基汞诱导神经元毒性的机制

基本信息

批准号：
9275984
负责人：
Michael Aschner
金额：
$ 57.18万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-03-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275984
关键词：
Acute Address Affect Anatomy Architecture Attenuated Biological Models Caenorhabditis elegans Calcium Cell model Cellular Stress Development Disease Enhancers Environmental Risk Factor Experimental Designs Exposure to Faeroe Islands Functional disorder Genes Genetic Genetic Predisposition to Disease Genetic Screening Genetic Variation Glutamates Goals Green Fluorescent Proteins Growth Homeostasis Human Human Genetics Impairment In Vitro Label Link Maps Measures Mediating Methylmercury Compounds Mitochondria Mitotic Modeling Molecular Nematoda Nervous System Trauma Nervous system structure Neuraxis Neurodegenerative Disorders Neurodevelopmental Disorder Neurologic Neurons Neurotoxins New Zealand Outcome Outcome Measure Oxidation-Reduction Oxidative Stress Pathologic Pathway interactions Pattern Play Predisposition Process RNA Interference RNA interference screen Research Resources Risk Role Seychelles Signal Transduction Synapses Testing Therapeutic Time Toxic effect Ursidae Family Variant base biological systems dopaminergic neuron experience exposed human population gene environment interaction gene interaction genetic approach genome-wide in vivo induced pluripotent stem cell innovation innovative technologies insight interdisciplinary approach methylmercury exposure mitochondrial dysfunction nervous system disorder neurogenetics neurotoxicity novel public health relevance relating to nervous system response sensor trait

项目摘要

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.

描述（由申请人提供）：甲基汞（MeHg）是一种强效神经毒素，影响发育和成熟的中枢神经系统（CNS），明显不加选择地破坏多种稳态途径。然而，遗传和环境改性剂对与人类接触相关的神经毒性有很大的变异性。本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，以减轻人类甲基汞暴露风险。在这里，我们提出了一个多方面的方法，结合强大的神经遗传模型系统，以人为基础的细胞和遗传方法，以提供新的疾病修改策略冲击甲基汞暴露的脆弱性，并使机制洞察遗传途径，修改特定的神经谱系的敏感性甲基汞诱导的神经毒性。具体来说，我们将测试的假设，改变易感性的遗传途径，甲基汞诱导的神经毒性将显示神经谱系和发育阶段依赖的活动。在具体目标1中，我们将在线虫C中筛选发育性甲基汞诱导的多巴胺能（DA能）和谷氨酸能（GLU能）神经毒性的遗传修饰剂。elegans，by RNAi.具体目标2中的研究将比较和对比甲基汞在人类黑质DA能和皮质Glu能神经谱系中的神经毒理学结果。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承担创新和互补的专业知识，以评估共享的遗传网络衰减甲基汞诱导的毒性与翻译外推从线虫到人类。