Gene-environment interactions between manganese exposure and Huntington disease

项目摘要/摘要 拟议工作的长期目标是了解环境和遗传因素是如何相互作用的。 影响选择性神经病理学。这项提案中包含的工作重点是 锰暴露对亨廷顿病(HD)病理生理学的影响锰的过度暴露一直是 与铁稳态和能量代谢的变化有关，并已被证明促进 固有的淀粉样蛋白的聚集。此外，锰在大脑中积累的一个主要部位是 纹状体，其中包含HD中最脆弱的神经元。慢性神经毒性应激 由突变的HD基因引起的疾病与铁稳态的改变、细胞内的缺陷有关 能量代谢，以及疾病蛋白积聚成淀粉样包涵体。这些相似之处在于 高锰症和锰神经毒性的病理生理学研究表明，锰暴露有可能调节高血压病。 神经病理学。利用国家环境卫生研究所提供的试点项目资源 范德比尔特大学分子毒理学核心科学中心，我们测试了 HD纹状体细胞模型上的锰暴露增加。这些试点实验揭示了一个令人惊讶的和 令人兴奋的结果是，突变的HD纹状体细胞对锰毒性具有抵抗力，并且与病理生理相关 暴露于锰会抑制突变的HD表型。这项提议将利用细胞和小鼠模型 疾病检查这种基因-环境神经保护相互作用的分子基础，并评估 锰暴露对HD发病机制的调节作用。这些研究围绕三个具体的 目标。首先，我们将定义特定HD蛋白结构域和特定细胞的贡献 功能结构域定位法研究锰在锰-HD基因-环境相互作用中的中介作用 评估具有类似神经毒性特性的其他金属。在第二个目标中，我们将确定锰离子是否会改变 用生物化学和生物物理方法研究HD蛋白的构象和功能性质 利用HD的细胞和动物模型。然后，在第三个目标中，我们将评估已知的病理终点 对锰毒性和HD神经病理学的研究，以阐明锰-HD的生理过程 活体内相互作用。这些具体目标与NIEHS的使命一致，因为他们审查了 一种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发病和进展的基因-环境界面，这项研究试图 揭示融合的遗传和环境因素如何增强或抑制的机制细节 疾病。项目叙事 随着人口老龄化，神经退行性疾病对个人、社会和经济的影响正在迅速增加。 升级。无论是环境毒物，如锰，还是遗传侮辱，如亨廷顿病， 导致疾病，但遗传和环境因素如何相互交织来调节疾病的作用尚不清楚 明白了。这项建议将研究发现的锰暴露和 亨廷顿氏病，有可能缓解人类疾病，优先治疗目标，以及 洞察选择性神经元变性的基础。

PROJECT SUMMARY/ABSTRACT 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 we 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 we 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 we 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 we 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. PROJECT NARRATIVE With an aging population the personal, social and economic impact of neurodegenerative disease is rapidly escalating. Both environmental toxicants, such as manganese, and genetic insults, as in Huntington's disease, contribute to disease, but how genetic and environmental factors intersect to modulate disease is poorly understood. This proposal will examine an interaction discovered between manganese exposure and Huntington's disease that has the potential to moderate human disease, prioritize therapeutic targets, and provide insight into the basis of selective neuronal degeneration.