Gene-Neurotoxicant Interactions in Huntington Disease

亨廷顿病中的基因-神经毒物相互作用

基本信息

批准号：
9021549
负责人：
Aaron B Bowman
金额：
$ 3.29万
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 2016-04-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9021549
关键词：
Address Affect Age of Onset Biological Biological Models Biology CAG repeat Cadmium Cell Line Cell model Cell physiology Cell-Mediated Cytolysis Cellular Stress Characteristics Chemicals Clinical Complex Corpus striatum structure Data Defect Development Disease Disease Progression Environment Environmental Health Environmental Risk Factor Enzymes Etiology Exhibits FRAP1 gene Floor Functional disorder Funding Genes Genetic Genetic Predisposition to Disease Genetic study Genotype Goals Health Histocompatibility Testing Homeostasis Human Huntington Disease Huntington gene Hypothalamic structure In Vitro Institutes Ions Length Link Manganese Maps Mediator of activation protein Metabolic Metals Methods Mitochondria Mus Nerve Degeneration Neurodegenerative Disorders Neurologic Symptoms Neurons Neurotoxins Onset of illness Outcome Oxidative Stress PARK2 gene Pathology Pathway interactions Patients Pattern Preclinical Testing Process Property Proto-Oncogene Proteins c-akt Publishing Reactive Oxygen Species Reporting Research Residual state Resistance Risk Assessment Role Signal Pathway Signal Transduction Specificity Stress System TP53 gene TSC1 gene Testing Toxic Environmental Substances Toxic effect Variant base biological adaptation to stress cell type clinically relevant cytotoxicity disease phenotype environmental agent environmental stressor excitotoxicity gene environment interaction high throughput screening illness length improved in vivo induced pluripotent stem cell inhibitor/antagonist innovation interdisciplinary approach mTOR Signaling Pathway mitochondrial dysfunction mouse model multidisciplinary mutant nerve stem cell neuropathology neurotoxic neurotoxicity novel outcome forecast personalized approach personalized medicine polyglutamine programs relating to nervous system research study response small molecule stem cell technology toxicant toxicant interaction

项目摘要

DESCRIPTION (provided by applicant): Huntington Disease (HD) is a neurodegenerative disorder pathologically characterized by selective degeneration of neurons within the striatum, cortex and hypothalamus. HD is caused by a CAG repeat expansion within the HTT gene, with longer repeats being strongly associated with earlier age-of-onset. Although repeat length explains over half of the variability in age of onset, a landmark genetic study attributed the majority of residual variability to unknown environmental factors. Metal ions with neurotoxic properties are strong candidates for environmental agents that may modulate selective neurodegenerative process like HD because, (1) the differential accumulation of various metals across neuronal subtypes, (2) the similarities between metal ion cytotoxicity and cellular pathways of neurodegeneration, and (3) our research in the previous funding cycle demonstrating altered vulnerability in mouse models of HD to both manganese and cadmium. The long-term goal of this research program is to reveal the pathogenic mechanisms underlying gene-environment interactions in neurodegenerative disease, focusing on HD given its clearly defined genetic etiology, to inform environmental health strategies to delay disease onset or slow the progression of disease. Our highly innovative approach combines (a) a novel high-throughput method to quantify cellular Mn status, (b) a state-of-the-art high throughput screen (HTS) facility at the Vanderbilt Institute of Chemical Biology (VICB), and (c) the clinical relevance of a patient-specific neuronal model system based on human induced pluripotent stem cell (hiPSC) technology. Aim 1 will test the hypothesis that an HD striatal Mn handling deficit discovered in the previous funding cycle will enable a HTS to find small molecules that mitigate the actions of HD environmental risk factors. Aim 2 will test the hypothesis that human striatal neuroprogenitors (NPs) from HD patients have increased sensitivity to non-cytotoxic levels of metal toxicants impinging upon specific stress response pathways. Aim 3 will test the clinical potential of small molecule modifiers of environmental risk factors in HD and whether the magnitude of HD-specific toxicant vulnerability will correlate by patient with established disease-modifiers such as neural lineage specificity, CAG-repeat length and clinical variation in age-of-onset. These specific aims will reveal disease-relevant environmental stress responses and identify small molecules to mitigate vulnerabilities and restore neuronal homeostasis in HD. Furthermore, discovery of toxicant interactions and patient-specific responses may inform environmental health strategies to delay disease onset or slow the progression of HD using a personalized medicine approach.

描述（由申请人提供）：亨廷顿病（HD）是一种神经退行性疾病，其病理学特征为纹状体、皮质和下丘脑内神经元的选择性变性。 HD 是由 HTT 基因内的 CAG 重复序列扩增引起的，较长的重复序列与较早的发病年龄密切相关。尽管重复长度解释了一半以上的发病年龄变异，但一项具有里程碑意义的遗传学研究将大部分残余变异归因于未知的环境因素。具有神经毒性的金属离子是调节 HD 等选择性神经退行性过程的环境剂的有力候选者，因为（1）不同金属在神经元亚型中的不同积累，（2）金属离子细胞毒性和神经退行性细胞途径之间的相似性，以及(3) 我们在上一个资助周期中的研究表明，HD 小鼠模型对锰和镉的脆弱性发生了改变。该研究项目的长期目标是揭示神经退行性疾病中基因与环境相互作用的致病机制，重点关注 HD 明确的遗传病因，为环境健康策略提供信息，以延缓疾病发作或减缓疾病进展。我们高度创新的方法结合了 (a) 一种新颖的高通量方法来量化细胞锰状态，(b) 范德比尔特化学生物学研究所 (VICB) 最先进的高通量筛选 (HTS) 设施，以及(c) 基于人类诱导多能干细胞 (hiPSC) 技术的患者特异性神经元模型系统的临床相关性。目标 1 将检验以下假设：在上一个资助周期中发现的 HD 纹状体锰处理缺陷将使 HTS 能够找到减轻 HD 环境风险因素作用的小分子。目标 2 将检验以下假设：HD 患者的人类纹状体神经祖细胞 (NP) 对影响特定应激反应途径的非细胞毒性水平的金属毒物的敏感性增加。目标 3 将测试 HD 环境危险因素的小分子调节剂的临床潜力，以及 HD 特异性毒物脆弱性的程度是否与具有已确定的疾病调节剂（例如神经谱系特异性、CAG 重复长度和临床变异）的患者相关。发病年龄。这些具体目标将揭示与疾病相关的环境应激反应，并识别小分子以减轻 HD 中的脆弱性并恢复神经元稳态。此外，毒物相互作用和患者特异性反应的发现可能会为环境健康策略提供信息，以使用个性化医疗方法延缓疾病发作或减缓 HD 的进展。