Human Microphysiological Model of Afferent Nociceptive Signaling

传入伤害性信号传导的人体微生理模型

• 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
• 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

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.

项目摘要 疼痛的管理 - 急性和慢性 - 对于两名患者来说都是令人沮丧的徒劳的努力 和临床医生。拼命用阿片类药物和其他麻醉品治疗的尝试导致了令人心碎的 处方止痛药成瘾的灾难性流行。这种流行促使联邦机构和 制药行业致力于识别下一代镇痛药。很遗憾， 目前，很少有足够的模型系统能够快速筛选镇痛性能 候选毒品。有用的下一代神经生理系统急需 用于识别候选药物诸如疼痛等问题。神经的大多数当前的微偶像类似模型 系统倾向于两类：类器官和微流体/微电极芯片。我们假设 神经系统的独特复杂性和结构需要一种综合方法，以实现 神经生理系统的设计，可以开始说明基本的生理单位 组装以产生神经系统的新兴行为。 我们建议开发一个基于人类细胞的基于人类细胞的传入疼痛途径的模型 脊髓。我们的方法具有创新性，因为它利用了新型的人类多能干细胞（HPSC）来源 将器官文化的3D性质与结构和组织结合的模型中的表型 微观制造系统的特异性，全部在一个集成的自定义3D微电极阵列上。由此产生的文化 平台将是背角传入电路的唯一可用人类模型。提案的目标 将分为两个阶段。首先，我们将建立与身体相关的人类，3D的可行性 传入疼痛途径的模型，可用于评估候选镇痛药。在第二个 阶段，我们将通过促进神经网络成熟来提高系统的身体相关性 在此之前，请演示系统的实用性，以建模阿片类药物的不良影响并筛选一个库 化合物以验证模型。目标的完成将建立新的方案来推导背侧 HPSC的角神经元，创建脊髓背角的第一个人类微生物生理模型 传入的感觉途径。