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-可以是一个令人沮丧的徒劳的奋进，为双方的病人 和临床医生。绝望地尝试用阿片类药物和其他麻醉剂治疗，导致了令人心碎的， 对处方止痛药上瘾的灾难性流行这种流行病促使联邦机构和 制药业致力于鉴定下一代止痛药。很不幸的是， 目前很少有足够的模型系统用于快速筛选 候选药物迫切需要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。目前大多数神经系统的微生理模型 系统趋向于两类：类器官和微流体/微电极芯片。我们假设， 神经系统独特的复杂性和结构需要一种综合的方法来实现 神经微生理系统的设计，可以开始解释基本的生理单位， 聚集起来产生神经系统的紧急行为。 我们建议建立一个基于人类细胞的模型，在背角的传入疼痛通路， 脊髓我们的方法是创新的，因为它利用了新的人类多能干细胞（hPSC）衍生的 表型的模型，结合了三维性质的类器官文化的结构和组织 微加工系统的特异性，所有这些都在集成的定制3D微电极阵列上。所得培养物 平台将是背角传入回路的唯一可用的人体模型。提案的目标 将分两个阶段进行。首先，我们将建立一个生理相关的，人类的，3D的可行性， 传入疼痛通路的模型，这将是有用的候选镇痛药物的评价。在第二 阶段，我们将通过促进神经网络成熟来改善系统的生理相关性 然后展示该系统在模拟阿片类药物的不良作用和筛选阿片类药物库方面的实用性。 化合物来验证模型。目标的完成将建立新的协议， 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