Human Microphysiological Model of Afferent Nociceptive Signaling

项目总结 疼痛的管理--无论是急性的还是慢性的--对这两位患者来说都是徒劳的，令人沮丧。 和临床医生。不顾一切地尝试用阿片类药物和其他麻醉剂治疗，导致了令人心碎和 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 制药行业致力于确定下一代止痛药。不幸的是， 目前很少有足够的模型系统用于快速筛选阿司匹林的止痛特性 毒品候选人。迫切需要下一代有用的神经微生理系统。 用于识别治疗疼痛等问题的候选药物。最新的神经微生理学模型 系统趋向于两类：有机物和微流控/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， 聚集在一起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，研究大鼠背角的传入痛觉通路。 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)来源 将器官培养的3D本质与结构和组织相结合的模型中的表型 微加工系统的特异性，所有这些都在一个集成的、定制的3D微电极阵列上。由此产生的文化 平台将是唯一可用的背角传入回路的人体模型。该提案的目标 将分两个阶段进行。首先，我们将建立一种与生理相关的3D人体 传入疼痛通路的模型，将有助于评估候选止痛药。在第二个 阶段，我们将通过促进神经网络的成熟来提高系统的生理相关性 在此之前，演示了该系统在阿片类药物不良影响建模和筛选库中的效用 化合物来验证该模型。该目标的完成将建立用于推导背部的新方案 并建立了第一个人类脊髓背角微生理学模型 传入感觉通路。

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.