Gene-Neurotoxicant Interactions in Huntington Disease

描述(申请人提供)：亨廷顿病(HD)是一种神经退行性疾病，病理特征是纹状体、皮质和下丘脑内的神经元选择性变性。HD是由HTT基因中CAG重复序列的扩张引起的，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发病年龄一半以上的变异性，但一项里程碑式的遗传研究将大部分残余变异性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选择性神经退变过程的环境因素的有力候选者，因为(1)各种金属在神经元亚型之间的差异积累，(2)金属离子细胞毒性与神经退变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。这项研究计划的长期目标是揭示神经退行性疾病中潜在的基因-环境相互作用的致病机制，重点关注HD，因为其明确的遗传病因，为环境卫生战略提供信息，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的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)技术的特定患者神经元模型系统的临床相关性。目标1将测试假设，即在前一个资金周期中发现的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前体细胞(NPs)对影响特定应激反应通路的非细胞毒性水平的金属毒物的敏感性增加的假设。目的3将测试环境危险因素的小分子修饰物在HD中的临床潜力，以及HD特异性毒物易损性的大小是否会与既定的疾病修饰物相关，如神经谱系特异性、CAG重复长度和发病年龄的临床变化。这些特定的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的脆弱性和恢复神经元的动态平衡。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卫生战略提供信息，以延迟疾病的发病或减缓HD的进展，使用个性化的药物方法。

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.