Gene-environment interactions between manganese exposure and Huntington disease

锰暴露与亨廷顿病之间的基因-环境相互作用

基本信息

批准号：
8077290
负责人：
Aaron B Bowman
金额：
$ 40.06万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8077290
关键词：
Amyloid Animal Model Award Biochemical Biological Biological Assay Brain Cell Line Cell model Cell physiology Cells Characteristics Chronic Complex Corpus striatum structure Data Deposition Disease Disease Progression Employee Strikes Energy Metabolism Environment Environmental Exposure Environmental Risk Factor Exposure to Functional disorder Genes Genetic Glutamine Goals Homeostasis Huntington Disease In Vitro Intervention Ions Iron Length Link Manganese Mediator of activation protein Mental disorders Metals Mission Mitochondria Modeling Molecular Molecular Conformation Molecular Toxicology National Institute of Environmental Health Sciences Nerve Degeneration Neurons Pathogenesis Pathology Pathway interactions Patients Physiological Physiological Processes Pilot Projects Process Property Proteins Proteolytic Processing Reporting Research Research Personnel Research Proposals Resistance Resources Route Signal Pathway Site Stress Tertiary Protein Structure Testing Toxic Environmental Substances Toxic effect Trinucleotide Repeats Universities Work base cell type cellular targeting clinically relevant defined contribution disease phenotype domain mapping gene environment interaction human Huntingtin protein human disease in vivo mouse model mutant neuropathology neuroprotection neurotoxic neurotoxicity novel protein aggregation research study

项目摘要

DESCRIPTION (provided by applicant) The long-term objective of the proposed work is to understand how environmental and genetic factors interact to influence selective neuropathology. The work contained within this proposal focuses on the influence of manganese (Mn) exposure on the pathophysiology of Huntington's disease (HD). Mn over-exposure has been associated with changes in iron homeostasis and energy metabolism, and has been shown to promote the aggregation of intrinsically amyloidogenic proteins. Furthermore, a major site of Mn accumulation in the brain is the corpus striatum, which contains the neurons most vulnerable in HD. The chronic neurotoxic stress rendered by the mutant HD gene has been associated with alterations in iron homeostasis, deficits in cellular energy metabolism, and accumulation of the disease protein into amyloid-like inclusions. These similarities in the pathophysiology of HD and Mn neurotoxicity suggest a potential for Mn exposure to modulate HD neuropathology. Using pilot project resources provided by the National Institute of Environmental Health Sciences (NIEHS) Core Center in Molecular Toxicology at Vanderbilt University, the investigators tested the influence of increased Mn exposure on a striatal cell model of HD. These pilot experiments revealed a surprising and exciting result, that mutant HD striatal cells are resistant to Mn toxicity and pathophysiologically relevant exposures to Mn suppress mutant HD phenotypes. This proposal will utilize cellular and mouse models of disease to examine the molecular basis of this gene-environment neuroprotective interaction and evaluate the potential of Mn exposure to modulate HD pathogenesis. These studies are organized around three specific aims. In the first of these the investigators will define the contribution of specific HD protein domains and specific cellular mediators of Mn action to the Mn-HD gene-environment interaction by functional domain mapping and evaluating other metals with similar neurotoxic properties. In the second aim the investigators will determine if Mn ions alter the conformational or functional properties of the HD protein by biochemical and biophysical protein assays utilizing cellular and animal models of HD. Then, in the third aim the investigators will evaluate known pathological endpoints of Mn toxicity and HD neuropathology to elucidate the physiological processes that underlie the Mn-HD interaction in vivo. These specific aims are aligned with the mission of the NIEHS in that they examine the impact of a specific environmental toxicant on the pathophysiological processes of human disease. Finally, by exploring a gene-environment interface that moderates the onset and progression of HD, this study seeks to reveal mechanistic detail for how convergent genetic and environmental factors can enhance or suppress disease.

描述（由申请人提供）拟议工作的长期目标是了解环境和遗传因素如何相互作用以影响选择性神经病理学。该提案中包含的工作重点是锰 (Mn) 暴露对亨廷顿病 (HD) 病理生理学的影响。锰过度暴露与铁稳态和能量代谢的变化有关，并已被证明可促进本质上淀粉样蛋白的聚集。此外，大脑中锰积累的主要部位是纹状体，其中包含 HD 中最脆弱的神经元。突变的 HD 基因造成的慢性神经毒性应激与铁稳态的改变、细胞能量代谢的缺陷以及疾病蛋白在淀粉样蛋白内含物中的积累有关。 HD 病理生理学和锰神经毒性的这些相似性表明，锰暴露有可能调节 HD 神经病理学。研究人员利用范德比尔特大学国家环境健康科学研究所 (NIEHS) 分子毒理学核心中心提供的试点项目资源，测试了增加锰暴露对 HD 纹状体细胞模型的影响。这些初步实验揭示了一个令人惊讶和令人兴奋的结果，即突变型 HD 纹状体细胞对锰毒性具有抵抗力，并且病理生理学相关的锰暴露会抑制突变型 HD 表型。该提案将利用疾病的细胞和小鼠模型来检查这种基因-环境神经保护相互作用的分子基础，并评估锰暴露调节 HD 发病机制的潜力。这些研究围绕三个具体目标进行。在第一个研究中，研究人员将通过功能域图谱和评估具有类似神经毒性特性的其他金属来定义特定 HD 蛋白域和 Mn 作用的特定细胞介质对 Mn-HD 基因-环境相互作用的贡献。在第二个目标中，研究人员将利用 HD 的细胞和动物模型通过生化和生物物理蛋白质测定来确定 Mn 离子是否改变 HD 蛋白质的构象或功能特性。然后，在第三个目标中，研究人员将评估锰毒性和 HD 神经病理学的已知病理学终点，以阐明体内 Mn-HD 相互作用的生理过程。这些具体目标与 NIEHS 的使命相一致，即研究特定环境毒物对人类疾病病理生理过程的影响。最后，通过探索调节 HD 发病和进展的基因-环境界面，本研究旨在揭示遗传和环境因素如何增强或抑制疾病的机制细节。