Gene-Neurotoxicant Interactions in Huntington Disease

亨廷顿病中的基因-神经毒物相互作用

• 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
• 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

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，其病理特征是纹状体、皮层和下丘脑内的神经元选择性变性。HD是由HTT基因内CAG重复扩增引起的，重复扩增时间越长与发病年龄越早密切相关。虽然重复长度解释了发病年龄变异的一半以上，但一项具有里程碑意义的遗传研究将大部分剩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可能调节HD等选择性神经退行性过程的环境因子的强有力候选者，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易感性发生了改变。该研究计划的长期目标是揭示神经退行性疾病中基因-环境相互作用的致病机制，重点研究HD，因为其明确定义的遗传病因，为环境健康策略提供信息，以延迟疾病的发生或减缓疾病的进展。我们高度创新的方法结合了(a)一种新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）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将验证假设，即在上一个资助周期中发现的HD纹状体Mn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。目的2将验证来自HD患者的人类纹状体神经祖细胞（NPs）对影响特定应激反应途径的非细胞毒性金属毒物的敏感性增加的假设。目的3将测试HD环境危险因素小分子修饰剂的临床潜力，以及HD特异性毒物易感程度是否与患者已建立的疾病修饰剂相关，如神经谱系特异性、cag重复序列长度和发病年龄的临床变化。这些特定的目标将揭示疾病相关的环境应激反应，并识别小分子以减轻HD的脆弱性和恢复神经元稳态。此外，毒物相互作用和患者特异性反应的发现可能为环境卫生策略提供信息，以使用个性化医疗方法延迟疾病发作或减缓HD的进展。