Multi-organ-on-chip device for modeling opioid reinforcement and withdrawal, and the negative affective component of pain: a therapeutic screening tool.

用于模拟阿片类药物强化和戒断以及疼痛的负面情感成分的多器官芯片设备：一种治疗筛选工具。

• 批准号: 10326436
• 负责人: Nureddin Ashammakhi
• 金额: $ 79.37万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10326436
• 关键词: 3-Dimensional; Acute; Agonist; Analgesics; Anhedonia; Biological Availability; Biological Models; Blood - brain barrier anatomy; Brain; Brain-Derived Neurotrophic Factor; Butyric Acids; Cells; Characteristics; Chemicals; Chronic; Clinical; Coculture Techniques; Complement; Detection; Development; Devices; Disinhibition; Dopamine; Drug Addiction; Drug Screening; Engineering; Epidemic; Exposure to; Future; Gene Expression; Gene Expression Profile; Genomic Library; Genomics; Goals; Human; Inflammatory; Intervention; Investigation; Libraries; Liver; Measures; Mediating; Metabolism; Microglia; Midbrain structure; Modeling; Molecular; Morphine; Neurobiology; Neuronal Plasticity; Neurons; Neurotransmitters; Online Systems; Opioid; Opioid Receptor; Opioid agonist; Output; Pain; Pain management; Pharmaceutical Preparations; Phase; Phosphotransferases; Process; Property; Proto-Oncogene Proteins c-akt; Psychological reinforcement; Psychopathology; Public Health; Relapse; Resource Sharing; Risk Factors; Role; Route; Scientist; Screening procedure; Signal Pathway; Specificity; System; Testing; Therapeutic; Therapeutic Intervention; Translating; Withdrawal; abuse liability; addiction; base; chemical resource; chronic pain; craving; design; drug of abuse; extracellular; gamma-Aminobutyric Acid; induced pluripotent stem cell; induced pluripotent stem cell technology; innovation; insight; kappa opioid receptors; kinase inhibitor; liver metabolism; metabolomics; microphysiology system; mu opioid receptors; negative affect; neurotransmission; new therapeutic target; novel; novel strategies; novel therapeutics; opioid abuse; opioid exposure; opioid use disorder; opioid withdrawal; organ on a chip; pain-related disability; prescription opioid; prescription opioid misuse; prevent; response; scaffold; screening; sensor; transcriptome sequencing; transmission process; treatment response

Abstract The significance of the public health crisis presented by the epidemic in opioid abuse is abundantly clear. There is a desperate need to develop therapeutics for treatment of opioid use disorder (OUD), and also to develop pain treatments that are non-addictive. Both of these goals will be served by high-throughput models amenable to drug screening, based on the use of human cells, that recapitulate features of the neurobiology underlying the addictive process. The model we propose to develop focuses on a key component of addictive circuitry – the dopaminergic and Gamma-Amino Butyric Acid (GABA)ergic neurons of the midbrain, long recognized as responsible for mediating the reinforcing properties of many classes of abused drugs, including opioids. We will develop multi-organ, microphysiological systems (MPSs) based on the use of human induced pluripotent stem cell (iPSC)-derived midbrain-fated dopamine (DA)/ GABA neurons on a three-dimensional platform that incorporates microglia, blood-brain-barrier (BBB) and liver metabolism components. RNA sequencing (RNAseq) and metabolomics analyses will complement the primary DA release measure to identify novel mechanisms contributing to chronic opioid-induced plasticity in DA responsiveness thought to underlie 1) the anhedonia characteristic of opioid withdrawal; 2) the negative affective component of chronic pain states; 3) craving and relapse. The chronic pain-relevant aspect of the model will be realized by examination of aversive kappa-mediated opioid effects on DA transmission in addition to the commonly abused mu opioid receptor agonists, and by incorporation of inflammatory-mediating microglia into the model. The incorporation of BBB and liver metabolism modules into the MPS platform will permit screening of drugs in the UH3 phase of the project that accounts for different routes of abused opioid administration and the bioavailability of potential therapeutic drugs, increasing translatability. Throughput will be increased by the integration of online sensors into the MPS for online detection of DA and other key analytes identified in the UG3 phase of the project. For addiction-treatment screening we will use a curated set of 100 chemical genomics probes from our UCLA kinase inhibitor library. The focus on kinases is based on their well-described role in plasticity, and will cover activities along the BDNF signaling pathway, mTORC2, mTORC1, AKT and other targets along the BDNF axis. Our selection of compounds/targets in this context will also be informed by the RNAseq and metabolomics results from the UG3 phase and we will supplement other drugs if needed from UCLA’s Molecular Screening Shared Resource chemical genomics libraries, which is over 3k probes strong. Although not proposed here, it is also important to point out that the MoC device could also be used to test the abuse liability of novel antinociceptive agents identified by other screening tools. With an interdisciplinary team of scientists and engineers, this proposal will build upon recent advances in organ-on-a-chip and iPSC technologies to create innovative MPSs with high potential to have significant clinical impacts in the future.

抽象的 阿片类药物滥用流行病造成的公共卫生危机的重要性是非常明显的。 迫切需要开发治疗阿片类药物使用障碍 (OUD) 的疗法，并 开发非成瘾性的疼痛治疗方法将通过高通量模型来实现。 适合基于人类细胞的使用进行药物筛选，概括神经生物学的特征 我们建议开发的模型侧重于成瘾的关键组成部分。 电路 – 中脑的多巴胺能和伽玛氨基丁酸 (GABA) 能神经元，长 被认为负责调节多种滥用药物的强化特性，包括 我们将开发基于人体诱导的多器官微生理系统（MPS）。 多能干细胞 (iPSC) 衍生的中脑命运多巴胺 (DA)/GABA 神经元在三维 整合了小胶质细胞、血脑屏障（BBB）和肝脏代谢成分的平台。 测序 (RNAseq) 和代谢组学分析将补充主要 DA 释放测量，以确定 导致慢性阿片类药物诱导的 DA 反应可塑性的新机制被认为是 1) 的基础 阿片类药物戒断的快感缺失特征；2) 慢性疼痛状态的负面情感成分； 3) 渴望和复发将通过检查来实现模型的慢性疼痛相关方面。 除了常见滥用的 mu 阿片类药物外，kappa 介导的阿片类药物对 DA 传输的厌恶作用 受体激动剂，以及将炎症介导的小胶质细胞纳入模型。 将 BBB 和肝脏代谢模块纳入 MPS 平台将允许在 UH3 阶段筛选药物 该项目解释了滥用阿片类药物的不同给药途径以及潜在的生物利用度 治疗药物，增加可翻译性将通过在线传感器的集成来提高。 进入 MPS，用于在线检测 DA 和项目 UG3 阶段确定的其他关键分析物。 成瘾治疗筛查，我们将使用来自 UCLA 的一组精选的 100 个化学基因组探针 激酶抑制剂库。对激酶的关注基于其在可塑性中的充分描述的作用，并将涵盖 BDNF 信号通路、mTORC2、mTORC1、AKT 和其他沿 BDNF 轴的靶标的活性。 我们在此背景下选择的化合物/靶点也将受到 RNAseq 和代谢组学的影响 UG3阶段的结果，如果需要，我们将补充来自加州大学洛杉矶分校分子筛选的其他药物 共享资源化学基因组库，其探针数量超过 3k，虽然这里没有提出，但它是强大的。 还需要指出的是，MoC 设备还可用于测试小说的滥用倾向 由跨学科科学家团队和其他筛选工具识别出的抗菌药物。 工程师们，该提案将建立在芯片器官和 iPSC 技术的最新进展的基础上，以创建 创新的 MPS 很有可能在未来产生重大的临床影响。