Gene-environment interactions between manganese exposure and Huntington disease

描述(由申请人提供) 这项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来影响选择性神经病理学。这项提案中包含的工作重点是接触锰对亨廷顿病(HD)的病理生理学的影响。锰过量暴露与铁稳态和能量代谢的变化有关，并已被证明促进固有淀粉样蛋白的聚集。此外，大脑中锰积累的一个主要部位是纹状体，它包含了HD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包涵体中的积聚有关。HD和Mn神经毒性在病理生理学上的这些相似之处表明，暴露于Mn有可能调节HD神经病理。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，研究人员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，突变的HD纹状体细胞对锰毒性和与锰相关的病理生理暴露抑制突变的HD表型。这项建议将利用细胞和小鼠疾病模型来检查这种基因-环境神经保护相互作用的分子基础，并评估暴露于锰在调节HD发病机制方面的潜力。这些研究围绕三个具体目标展开。首先，研究人员将通过功能结构域的定位和对其他具有类似神经毒性特性的金属的评估，来确定特定的HD蛋白结构域和特定的细胞介质对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分析来确定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，研究人员将评估已知的锰中毒的病理终点和HD神经病理学，以阐明体内Mn-HD相互作用的生理过程。这些具体目标与NIEHS的使命一致，因为它们审查了特定环境毒物对人类疾病的病理生理过程的影响。最后，通过探索缓和HD发病和发展的基因-环境界面，本研究试图揭示遗传和环境因素如何聚合可以增强或抑制疾病的机制细节。

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.