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）：亨廷顿疾病（HD）是一种神经退行性疾病，其病理学的特征是纹状体，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重复扩展引起的，其重复较长与早期年龄相关。尽管重复长度解释了发病年龄变化的一半以上，但具有里程碑意义的遗传研究将大多数残余变异性归因于未知的环境因素。具有神经毒性特性的金属离子是可能调节选择性神经退行性过程（如HD）的环境药物的强大候选物锰和镉。该研究计划的长期目标是揭示神经退行性疾病中基因 - 环境相互作用的基础病理机制，鉴于其明确定义的遗传病因，以延迟疾病开始或减缓疾病进展，侧重于HD。我们高度创新的方法结合了（a）一种新型的高通量方法来量化细胞MN状态，（b）范德比尔特化学生物学研究所（VICB）的最先进的高通量筛选（HTS）设施，以及（c）基于人类诱导的Pluripotent pluripotent（Hipsccc）的患者神经元模型系统的临床相关性。 AIM 1将检验以下假设：在上一个资金周期中发现的HD纹状体MN处理赤字将使HTS能够找到减轻HD环境风险因素的作用的小分子。 AIM 2将检验以下假设：来自HD患者的人纹状体神经源性剂（NP）对撞击特定应激反应途径的金属毒物的非毒性水平的敏感性提高。 AIM 3将测试HD环境危险因素的小分子修饰剂的临床潜力，以及HD特异性毒物脆弱性的大小是否会与已建立疾病模拟器的患者相关，例如神经谱系特异性，例如CAG重复的长度和临床变异。这些具体目的将揭示与疾病相关的环境压力反应，并确定小分子以减轻脆弱性并恢复HD中的神经元体内平衡。此外，发现有毒物质相互作用和特定于患者的反应可能会为环境健康策略提供信息，以延迟疾病的发作或使用个性化医学方法降低HD的发展。