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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：
7890954
负责人：
Aaron B Bowman
金额：
$ 10.16万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-17 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7890954
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）