Human Microphysiological Model of Afferent Nociceptive Signaling

传入伤害性信号传导的人体微生理模型

基本信息

批准号：
10348860
负责人：
Randolph S Ashton
金额：
$ 197.89万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-26 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348860
关键词：
3-Dimensional Acute Acute pain management Adverse effects Analgesics Behavior Biological Models Categories Cells Chronic Custom Drug Industry Electric Stimulation Engineering Epidemic Evaluation Human Libraries Microelectrodes Microfluidics Microglia Modeling Narcotics Nature Nervous system structure Neuroglia Neuromodulator Nociception Opioid Organoids Pain Pain management Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Physiological Play Posterior Horn Cells Property Protocols documentation Rapid screening Role Sensory Signal Transduction Specificity Spinal Spinal Cord Spinal cord posterior horn Structure System Technology Testing Work addiction base biofabrication body system chronic pain design dorsal horn drug candidate human model human pluripotent stem cell improved innovation microphysiology system neural network neuroregulation next generation novel opiate tolerance pain model pain relief pain signal public health relevance relating to nervous system screening three-dimensional modeling transmission process

项目摘要

PROJECT SUMMARY The management of pain—both acute and chronic—can be a frustratingly futile endeavor for both patients and clinicians. Desperate attempts at treatment with opioids and other narcotics has led to a heartbreaking and calamitous epidemic of addiction to prescription painkillers. This epidemic has prompted federal agencies and the pharmaceutical industry to work toward the identification of the next generation of analgesics. Unfortunately, there are few adequate model systems currently in use to enable rapid screening of the analgesic properties of drug candidates. There is an acute need for next-generation neural microphysiological systems that are useful for identifying drug candidates for problems such as pain. Most current microphysiogical models of the nervous system tend toward two categories: organoids and microfluidic/ microelectrode chips. We postulate that the unique complexity and structure of the nervous system demand an integrated approach in order to realize designs of neural microphysiological systems that can begin to account for the basic physiological units that assemble to produce emergent behaviors of the nervous system. We propose to develop a human cell-based model of the afferent pain pathway in the dorsal horn of the spinal cord. Our approach is innovative because it utilizes novel human pluripotent stem cell (hPSC)-derived phenotypes in a model that combines the 3D nature of organoid culture with the structural and organizational specificity of microfabricated systems, all on an integrated, custom 3D microelectrode array. The resulting culture platform will be the only available human model of the dorsal horn afferent circuit. The objectives of the proposal will be met in two phases. In the first, we will establish the feasibility of a physiologically relevant, human, 3D model of the afferent pain pathway that will be useful for evaluation of candidate analgesic drugs. In the second phase, we will then improve the physiological relevance of the system by promoting neural network maturation before then demonstrating the system’ utility in modeling adverse effects of opioids and screening a library of compounds to validate the model. Completion of the objective will establish novel protocols for deriving dorsal horn neurons from hPSCs and create the first human microphysiological model of the spinal cord dorsal horn afferent sensory pathway.

项目概要治疗疼痛（无论是急性还是慢性）对于患者来说都是徒劳的，令人沮丧和圣徒们绝望地尝试使用阿片类药物和其他麻醉剂进行治疗，导致了令人心碎和痛苦的结果。处方止痛药成瘾的灾难性流行已促使联邦机构和机构采取行动。制药行业致力于鉴定下一代镇痛药。目前很少有足够的模型系统能够快速筛选镇痛特性迫切需要有用的下一代神经微生理系统。用于识别治疗疼痛等问题的候选药物。最新的神经微生理模型。系统倾向于两类：类器官和微流体/微电极芯片。神经系统独特的复杂性和结构需要一种综合方法才能实现神经微生理系统的设计可以开始解释基本的生理单位聚集以产生神经系统的紧急行为。我们建议开发一种基于人类细胞的背角传入疼痛通路模型我们的方法是创新的，因为它利用了新型人类多能干细胞 (hPSC) 衍生的。模型中的表型将类器官培养的 3D 性质与结构和组织相结合微加工系统的特异性，全部位于集成的定制 3D 微电极阵列上。平台将成为唯一可用的背角传入回路的人体模型该提案的目标。将分两个阶段实现。第一阶段，我们将建立生理相关的人体 3D 的可行性。传入疼痛通路模型将有助于评估候选镇痛药物。阶段，我们将通过促进神经网络成熟来提高系统的生理相关性然后展示该系统在模拟阿片类药物不良反应和筛选阿片类药物库方面的实用性验证模型的化合物将建立用于衍生背侧的新方案。来自 hPSC 的角神经元并创建第一个人类脊髓背角微生理模型传入感觉通路。