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

皮肤神经元感觉触觉器官的生物物理学及其对机械和化学应力的敏感性

基本信息

批准号：
10176122
负责人：
Miriam B Goodman
金额：
$ 17.1万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10176122
关键词：
Acute Pain Affect Afferent Neurons Analgesics Animal Model Animals Aspirin Behavior Behavioral Biochemistry Biological Assay Biophysics Caenorhabditis elegans Chemicals Chemotaxis Defect Dependence Development Drug Targeting Esthesia Expression Profiling Funding G-Protein-Coupled Receptors Gene Expression Genes Genetic Genetic study Genome Genomics Goals Homologous Gene Homologous Protein Human Human Genome Impairment Invertebrates Ion Channel Knowledge Lead Libraries Ligands Link Mechanics Medicinal Plants Membrane Membrane Potentials Membrane Proteins Mining Modeling National Institute of Neurological Disorders and Stroke Natural Products Nematoda Nervous system structure Neurons Nociception Nociceptive Stimulus Nociceptors Opioid Opioid agonist Organ Orthologous Gene Outcome Pain Pain management Pathway Analysis Pharmacotherapy Phenotype Plants Play Property Proteins Public Health Receptor Activation Research Research Project Grants Role Skin Source Specific qualifier value Stress Tactile Testing Therapeutic Agents Therapeutic Uses addiction base behavioral study chronic pain genetic approach improved innovation kappa opioid receptors member mutant nociceptive response non-opioid analgesic novel novel therapeutics opioid use opioid use disorder overexpression pain relief pre-clinical receptor response screening small molecule socioeconomics therapeutic development

项目摘要

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.

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。