PDF(Pubmed)
Abstract：
The detection and avoidance of harmful stimuli are essential animal capabilities. The molecular and cellular mechanisms controlling nociception and its plasticity are conserved, genetically controlled processes of broad biomedical interest given their relevance to understand and treat pain conditions that represent a major health burden. Recent genome-wide association studies (GWAS) have identified a rich set of polymorphisms related to different pain conditions and pointed to many human pain gene candidates, whose connection to the pain pathways is however often poorly understood. Here, we used a computer-assisted Caenorhabditis elegans thermal avoidance analysis pipeline to screen for behavioral defects in a set of 109 mutants for genes orthologous to human pain-related genes. We measured heat-evoked reversal thermosensitivity profiles, as well as spontaneous reversal rate, and compared naïve animals with adapted animals submitted to a series of repeated noxious heat stimuli, which in wild type causes a progressive habituation. Mutations affecting 28 genes displayed defects in at least one of the considered parameters and could be clustered based on specific phenotypic footprints, such as high-sensitivity mutants, nonadapting mutants, or mutants combining multiple defects. Collectively, our data reveal the functional architecture of a network of conserved pain-related genes in C. elegans and offer novel entry points for the characterization of poorly understood human pain genes in this genetic model.
摘要：
检测和避免有害刺激是动物的基本能力。控制伤害感受的分子和细胞机制及其可塑性是保守的，遗传控制的过程具有广泛的生物医学兴趣，因为它们与理解和治疗代表主要健康负担的疼痛状况有关。最近的全基因组关联研究（GWAS）已经确定了一组与不同疼痛状况相关的丰富的多态性，并指出许多人类疼痛基因候选。然而，他们与疼痛途径的联系往往知之甚少。这里,我们使用计算机辅助C.elegans热回避分析流程,在一组109个与人类疼痛相关基因直系同源的突变体中筛选行为缺陷.我们测量了热诱发反转热敏感性曲线，以及自发逆转率，并将幼稚的动物与适应的动物进行了一系列反复的有害热刺激的比较，在野生型中会导致逐渐的习惯。影响28个基因的突变在至少一个考虑的参数中显示出缺陷，可以根据特定的表型足迹进行聚类，比如高灵敏度突变体，非适应性突变体或组合多个缺陷的突变体。总的来说，我们的数据揭示了秀丽隐杆线虫中保守的疼痛相关基因网络的功能结构,并为该遗传模型中对人类疼痛基因的表征提供了新的切入点.
