The biophysics of skin-neuron sensory tactile organs and their sensitivity to mechanical and chemical stress

疼痛是一个广泛而持久的公共卫生问题，伴随着无数的社会经济问题 后果，包括成瘾和阿片类药物使用障碍。许多治疗疼痛的药物 今天的管理起源于植物，从阿司匹林到鸦片类药物。尽管如此，大多数植物还是来自 化合物的生物活性还没有得到广泛的研究，包括许多 由药用植物合成。本申请已提交至PA-18-591，以回应 NOT-TR-20-008，呼吁研究可用药人类中未被研究的蛋白质 基因组有可能成为治疗疼痛的新靶点。我们建议 建立快速研究渠道，将植物衍生化合物与伤害(疼痛)和 到可用药的人类基因组中的GPCRs和离子通道。因为其中80%以上 线虫的膜蛋白是保守的，这种模式生物是一个被证实的平台 对于表型筛选，我们建议筛选影响伤害性感受的化合物和基因 以及利用线虫鉴定新的配体-受体对。我们将首先链接 植物衍生化合物对热伤害性感受器的调制作用 未被研究但保守的GPCRs和离子通道参与了伤害性感受。 进入点化合物的存在或不存在(目标1)和Next利用线虫 化学感觉神经元表达多个GPCRs，这些受体的激活导致 吸引或排斥行为(目标2)。这项创新的研究项目具有 确定特定基因在伤害性感受中的功能并揭示新的 配基-受体对可以作为改善或替代疼痛的新切入点 治疗。

Pain is a widespread and persistent public health problem with myriad socio-economic ramifications, including addiction and opiate use disorders. Many therapeutics used for pain management today have their origins in plants, from aspirin to opiates. Still, most plant derived compounds have not been studied extensively for their bioactivity, including many that are synthesized by medicinal plants. This application is submitted to PA-18-591 in response to NOT-TR-20-008, a call for studies to characterize understudied proteins in the druggable human genome with the potential to serve as new targets for the treatment of pain. We propose to establish a rapid research pipeline for linking plant-derived compounds to nociception (pain) and to GPCRs and ion channels in the druggable human genome. As more than 80% of these membrane proteins are conserved in C. elegans and this model organism is a proven platform for phenotypic screens, we propose screens for compounds and genes affecting nociception as well as to identify novel ligand-receptor pairs using C. elegans nematodes. We will first link plant-derived compounds to modulation of thermal nociceptors and then to determine which of the understudied, but conserved GPCRs and ion channels are involved in nociception in the presence or absence of entry point compounds (Aim 1) and next exploit the fact that C. elegans chemosensory neurons express multiple GPCRs and that activation of these receptors causes either attraction or repulsion behaviors (Aim 2). This innovative research project has the potential to determine the function of the specified genes in nociception and to reveal novel ligand-receptor pairs that could serve as new entry points for improved or alternative pain treatments.