Gene-Neurotoxicant Interactions in Huntington Disease

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重复扩增引起的，较长的重复与较早的发病年龄密切相关。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。具有神经毒性性质的金属离子是可调节选择性神经变性过程（如HD）的环境剂的强候选者，因为（1）各种金属在神经元亚型之间的差异性积累，（2）金属离子细胞毒性与神经变性的细胞途径之间的相似性，以及（3）我们在上一个资助周期的研究表明，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，重点关注HD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）一种新的高通量方法来定量细胞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。目的1将测试的假设，即在前一个资金周期中发现的HD纹状体锰处理赤字将使HTS找到小分子，减轻HD环境风险因素的作用。目的2将测试的假设，人类纹状体神经祖细胞（NP）从HD患者有增加的敏感性非细胞毒性水平的金属毒物冲击特定的应激反应途径。目的3将测试HD中环境风险因素的小分子修饰剂的临床潜力，以及HD特异性毒物易感性的大小是否与患者的已建立疾病修饰剂相关，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。这些具体的目标将揭示疾病相关的环境应激反应，并确定小分子，以减轻脆弱性和恢复神经元的稳态在HD。此外，毒物相互作用和患者特异性反应的发现可以为环境健康策略提供信息，以使用个性化药物方法延迟疾病发作或减缓HD进展。

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.